Transcatheter Intervention for Coarctation of the Aorta: A Nordic Population-Based Registry With Long-Term Follow-Up.

BACKGROUND: Coarctation of the aorta (CoA), a congenital narrowing of the proximal descending thoracic aorta, is a relatively common form of congenital heart disease. Untreated significant CoA has a major impact on morbidity and mortality. In the past 3 decades, transcatheter intervention (TCI) for CoA has evolved as an alternative to surgery. OBJECTIVES: The authors report on all TCIs for CoA performed from 2000 to 2016 in 4 countries covering 25 million inhabitants, with a mean follow-up duration of 6.9 years. METHODS: During the study period, 683 interventions were performed on 542 patients. RESULTS: The procedural success rate was 88%, with 9% considered partly successful. Complications at the intervention site occurred in 3.5% of interventions and at the access site in 3.5%. There was no in-hospital mortality. During follow-up, TCI for CoA reduced the presence of hypertension significantly from 73% to 34%, but despite this, many patients remained hypertensive and in need of continuous antihypertensive treatment. Moreover, 8% to 9% of patients needed aortic and/or aortic valve surgery during follow-up. CONCLUSIONS: TCI for CoA can be performed with a low risk for complications. Lifetime follow-up after TCI for CoA seems warranted.

Liver fibrosis in patients with tetralogy of Fallot, an unrecognised complication?

OBJECTIVES: Improved survival has led to a growing population of adults with congenital heart disease (CHD), followed by numerous reports of late complications. Liver disease is a known complication in some patients, with most studies focusing on Fontan associated liver disease. Whether liver disease also exists in other patients with CHD is not fully investigated. Elevated central venous pressure is considered pivotal in the development of liver disease in Fontan associated liver disease, and other patients with alterations in central venous pressure may also be at risk for developing liver fibrosis. We wanted to see if liver fibrosis is present in patients with tetralogy of Fallot. Many patients with tetralogy of Fallot have severe pulmonary regurgitation, which can lead to elevated central venous pressure. Patients with tetralogy of Fallot may be at risk of developing liver fibrosis. MATERIALS AND METHODS: Ten patients (24-56 years) with tetralogy of Fallot and pulmonary regurgitation were investigated for liver fibrosis. All patients were examined with magnetic resonance elastography of liver, hepatobiliary iminodiacetic acid scan, indocyanine green elimination by pulse spectrophotometry, elastography via FibroScan, abdominal ultrasound including liver elastography, and blood samples including liver markers. RESULTS: Three out of ten patients had findings indicating possible liver fibrosis. Two of these had a liver biopsy performed, which revealed fibrosis stage 1 and 2, respectively. The same three patients had an estimated elevated central venous pressure in previous echocardiograms. CONCLUSIONS: Mild liver fibrosis was present in selected patients with tetralogy of Fallot and may be related to elevated central venous pressure.

Intravascular assessment of coronary arteries in patients with cyanotic congenital heart disease.

AIMS: Patients with cyanotic congenital heart disease (CCHD) have been suggested to develop less atherosclerosis than the general population. This study aimed to evaluate the extent of coronary atherosclerosis in patients with CCHD using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS). METHODS AND RESULTS: Fifteen patients with CCHD (women, 9; median age, 53 years) and 14 acyanotic controls (women, 6; median age, 53 years) were examined with IVUS-NIRS of the right coronary artery (RCA). The patients with CCHD presented with a larger RCA diameter than the controls (external elastic membrane diameter, 6.1 [4.8-6.7] vs. 4.7 [4.1-5.1] mm, respectively; p=0.01). No difference in area stenosis was found between the patients and the controls (15.8% [12.3-19.7] vs. 15.2% [9.5-18.8]; p=0.87). The presence of lipid by NIRS was noted in 43% of patients with CCHD and in 92% of the controls; however, no differences in total or max 4 mm lipid core burden index (LCBI) or in plasma lipid profile were found. CONCLUSIONS: Patients with CCHD presented with larger coronary arteries than acyanotic controls. No difference in the degree of area stenosis in the coronary arteries was found between the cyanotic and acyanotic patients; however, a lower proportion of patients with CCHD showed a positive LCBI.

Subclinical hypothyroidism: A common finding in adult patients with cyanotic congenital heart disease.

OBJECTIVE: Cyanotic congenital heart disease is a systemic disease, with effects on multiple organ systems. A high prevalence of subclinical hypothyroidism (SCH) has been reported in a small cohort of cyanotic congenital heart disease patients. Subclinical hypothyroidism has been associated with various adverse cardiovascular effects, as well as an increased risk of progression to overt hypothyroidism. The aim of this study was to examine the prevalence of SCH in cyanotic congenital heart disease patients, consider possible etiologies, and evaluate thyroid function over time. METHODS: First, 90 clinically stable cyanotic congenital heart disease patients were examined with blood samples (thyroid-stimulating hormone, C-reactive protein, hemoglobin, hematocrit, and N-terminal pro-brain-natriuretic peptide) in a cross-sectional descriptive study. Second, a longitudinal follow-up study of 43 patients originating from the first study part, was carried out. These patients had thyroid function parameters (thyroid-stimulating hormone, thyroid hormones, and thyroid peroxidase antibodies) evaluated biannually. RESULTS: Elevated thyroid-stimulating hormone was present in 24% of the 90 screened patients. During follow-up (6.5 ± 1.0 years), SCH (defined as ≥2 consecutive elevated thyroid-stimulating hormone values) was present in 26%. Three patients progressed to overt hypothyroidism. Patients with SCH were younger (34 ± 12 vs 42 ± 16 years; P = .01) and had a lower oxygen saturation (80 ± 5 vs 84 ± 6%; P = .03). CONCLUSION: Subclinical hypothyroidism is a very common finding in cyanotic congenital heart disease. This is not associated with increased levels of C-reactive protein, heart failure, or autoimmunity but appears to be associated with cyanosis and age. Since the clinical impact of SCH is uncertain, further studies are needed to determine this. Regular thyroid evaluation is recommended in cyanotic congenital heart disease patients since SCH can develop to overt hypothyroidism.

Advanced Therapy in Eisenmenger Syndrome: A Systematic Review.

Treatment options for patients with the Eisenmenger syndrome have until recently been scarce, but new knowledge in the field of pulmonary arterial hypertension has expanded the therapeutic possibilities for these patients. Advanced therapy with pulmonary vasodilators has become part of the standard treatment, offering long-term benefits on exercise capacity, clinical symptoms, and possibly survival. However, there are currently only few studies to guide the use of advanced therapies in this population, and important questions such as indications for initiation or escalation of advanced therapy and valid effect parameters and treatment goals remain unanswered. This review covers the pharmacology, therapeutic options, risk stratification, and treatment strategy of pulmonary arterial hypertension-specific drugs in patients with Eisenmenger syndrome.

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.

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 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.

Hemodynamic causes of exercise intolerance in Fontan patients.

BACKGROUND: Exercise intolerance is frequent among Fontan patients and an important determinant for quality of life. This study investigated the hemodynamic causes of impaired exercise capacity in Fontan patients with particular focus on the influence of stroke volume index (SVI) and heart rate (HR). METHODS AND RESULTS: In 38 Fontan patients, peak oxygen consumption (VO2), SVI and HR were recorded during incremental load exercise test and compared with 19 age and gender matched controls. SVI (ml/m(2)) was lower in patients than controls during warm-up (28[26-31] vs. 35[30-39], p=0.0093), at submaximal (40[37-43] vs. 55[51-59], p<0.0001) and at maximal exercise (38[35-40] vs. 54[51-58], p<0.0001). Similarly, HR (% of expected maximum) was lower in patients at warm-up (45[43-48]% vs. 64[57-64]%, p<0.0001), submaximal (71[68-75]% vs 85[82-88]%, p<0.0001) and maximal exercise (84[80-88]% vs. 97[95-99]%, p<0.0001). Furthermore, SVI dropped 14% (from 44[41-48] to 38[35-40] ml/m(2)) in Fontan patients from the peak plateau to maximal exercise vs. 5% (from 57[53-61] to 54[51-58] ml/m(2)) in controls, p<0.0001. The low SVI and HR explained 67% and 20% of the difference in peak VO2 between Fontan patients and controls respectively. CONCLUSION: SVI decreased significantly in Fontan patients near the end of maximal effort exercise. The low SVI at maximal exercise was the most important hemodynamic factor limiting exercise capacity in Fontan patients, whereas chronotropic impairment had a smaller impact. The low SVI and HR at maximal exercise accounted for the difference in peak VO2 between Fontan patients and controls in this study. CLINICAL TRIAL REGISTRATION: http://www.cvk.sum.dk/CVK/Home/English.aspx (protocol nr: H-3-2010-045).

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.

The effect of bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study.

BACKGROUND: Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC).An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients. METHODS/DESIGN: The TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life. DISCUSSION: We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients.

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.

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.

Impact of fixed pulmonary hypertension on post-heart transplant outcomes in bridge-to-transplant patients.

BACKGROUND: Fixed pulmonary hypertension (FPH) is considered a contraindication to cardiac transplantation. Ventricular assist device (VAD) therapy through prolonged left ventricular unloading may reverse FPH. Our aim was to assess post-transplant outcomes and survival in patients with and without FPH undergoing VAD implantation as bridge to transplant. METHODS: Fifty-four patients received an intracorporeal left VAD (LVAD) as a bridge to transplant from 2000 to 2008 at two institutions (Rigshospitalet, Denmark, and the Toronto General Hospital, Canada). Twenty-two (41%) patients had fixed FPH (defined as pulmonary vascular resistance [PVR] >3 Wood units and resistant to pulmonary vasodilators) prior to VAD implant (FPH group) and were compared with 32 patients without FPH (NoFPH group). Baseline characteristics, pre- and post-transplant pulmonary pressures, incidence of complications and post-transplant survival were analyzed. RESULTS: Baseline characteristics were similar except that patients in the FPH group were older (46 ± 11 years vs 39 ± 13 years in the NoFPH group, p < 0.05). The mean pre-VAD PVR was 4.3 ± 1.7 Wood units in the FPH group and 1.7 ± 0.5 Wood units in the NoFPH group (p < 0.001). Pulmonary pressures were higher in the FPH group immediately prior to VAD implant, but they were comparable immediately pre-transplant and during the first year post-transplant. The incidence of post-transplant RV failure was not significantly different between groups. Post-transplant survival was similar between groups. CONCLUSIONS: VAD therapy successfully decreases pulmonary hypertension, even in patients with "fixed" FPH, allowing candidacy for heart transplantation. Among bridge-to-transplant candidates, the presence of FPH does not reduce post-transplant survival.

Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial.

AIMS: To evaluate the efficacy of combining the dual endothelin receptor antagonist, bosentan, and the phosfodiesterase-5-inhibitor, sildenafil, in patients with Eisenmenger syndrome. METHODS AND RESULTS: The study was a randomized, placebo-controlled, double-blinded, cross-over design. Patients with Eisenmenger syndrome (n = 21) were treated open label with bosentan for 9 months. After 3 months, sildenafil/placebo was added for 3 months, and a cross-over was performed for the last 3 months. At baseline and after 3, 6, and 9 months, patients were examined with 6 min walk test, oxygen saturations, N-terminal pro-brain natriuretic peptide, New York Heart Association (NYHA) classification, cardiac catheterization, and magnetic resonance imaging. The primary endpoint was changed in 6 min walk distance (MWD). Bosentan improved the 6 MWD (377 vs. 414 m, P = 0.001), pulmonary vascular resistance (PVR) (28 vs. 22 wood, P = 0.01), and pulmonary blood flow (2.6 vs. 3.5 L/min, P = 0.01). Adding sildenafil to bosentan did not improve the 6 MWD significantly (21 vs. 8 m, P = 0.48), but increased saturation at rest (2.9 vs. -1.8%, P < 0.01). CONCLUSION: In Eisenmenger syndrome, treatment with bosentan significantly improved walking distance, pulmonary blood flow, and PVR. Adding sildenafil to bosentan did not significantly improve walking distance but did increase saturation at rest. http://www.ClinicalTrial.gov: NCT00303004.

The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab.

OBJECTIVE: This study examined the effects of anti-thymocyte globulin (ATG) and daclizumab immunosuppressive induction therapy on the frequency and severity of acute cellular rejection in lung transplantation patients. METHOD: A retrospective analysis was conducted of 335 lung transplantation patients from a single center in the period 1992 to 2003. Patients completed standard ATG (Merieux, 2.5 mg/kg/day, or ATGAM, 12.5 mg/kg/day, for 3 consecutive days) (n = 151) or daclizumab (5 fortnightly treatments at a dose of 1 mg/kg) (n = 151) induction therapy. End points included acute cellular rejection requiring treatment (> or = A2), and moderate/severe acute cellular rejection (A3/A4). RESULTS: The percentage of patients free of rejection requiring treatment (< A2) was 32% at 3 months and 26% at 2 years after transplantation in the ATG group and 9% and 0%, respectively, in the daclizumab group (p < 0.0001). Compared with the ATG group, a significantly higher proportion of patients in the daclizumab group experienced 3 or more episodes of acute cellular rejection > or = A2 during the first 3 months (p < 0.0001) and the entire 2-year follow-up (p < 0.0001). The daclizumab group also experienced more moderate/severe acute cellular rejection episodes compared with the ATG group during the first 3 months (p = 0.005). Cox regression analysis demonstrated ATG induction therapy was independently associated with a significantly longer duration of freedom from acute cellular rejection requiring treatment (> or = A2) (p < 0.001). CONCLUSION: After lung transplantation, ATG induction appears to be superior to daclizumab induction in the reduction in the incidence and severity of acute cellular rejection.