Anselm Uebing

Abnormal Ventilatory Response to Exercise in Adults With Congenital Heart Disease Relates to Cyanosis and Predicts Survival

Background— Limited data exist with which to stratify risk in adult congenital heart disease (ACHD). An increased ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production (&OV0312;e/&OV0312;co2 slope), is an established predictor of impaired survival in acquired heart disease. We sought to establish the distribution, relation to cyanosis, and prognostic value of the &OV0312;e/&OV0312;co2 slope across a wide spectrum of ACHD patients. Methods and Results— Five hundred sixty ACHD patients of varying diagnoses and 50 healthy controls underwent cardiopulmonary exercise testing at a single laboratory between 2001 and 2004. Patient age was 33.2±12.9 years (mean±SD). Peak oxygen consumption was 23.5±9.0 mL · kg−1 · min−1. &OV0312;e/&OV0312;co2 slope for all patients was 36.3±15.3. The slope was raised in all ACHD groups compared with controls and was 73% higher in cyanotic patients. Cyanosis, with or without pulmonary arterial hypertension, was the strongest predictor of abnormal &OV0312;e/&OV0312;co2 slope. The &OV0312;e/&OV0312;co2 slope was the most powerful univariate predictor of mortality in the noncyanotic group and the only independent predictor of mortality among exercise parameters on multivariate analysis. In cyanotic patients, no parameter was predictive of death. Conclusions— Ventilatory response to exercise is abnormal across the spectrum of ACHD. Cyanosis is a powerful stimulus for such exaggerated ventilatory patterns irrespective of the presence of pulmonary arterial hypertension. Increased &OV0312;e/&OV0312;co2 slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Pregnancy and congenital heart disease

Congenital heart disease occurs in 0.8% of newborn infants around the world. Advances in medical and surgical treatments over the past decades has led to more than 85% of these infants surviving to adulthood.1 2 Most interventions, however, have not been curative and about half of adults with congenital heart disease face the prospect of further surgery, arrhythmia, heart failure, and—if managed inappropriately—premature death. The burden of pregnancy represents a new challenge in women with congenital heart disease. In the United Kingdom about 250 000 adults have congenital heart disease (also known as “grown up congenital heart disease (GUCH)” patients), and this number is growing.3 Half of these patients are women, most of reproductive age. After suicide, cardiac disease is now the leading cause of maternal death in the UK, with most of these casualties having had congenital heart disease.4 The medical profession should therefore be aware of the risks that women with congenital heart disease face during pregnancy so that they can be given adequate preconception counselling and optimal care during pregnancy, delivery, and the postpartum period.5–7 Discussions about future pregnancies, family planning, and contraception should begin in adolescence to prevent accidental and potentially dangerous pregnancies in women with congenital heart disease. The impact of heart disease on childbearing potential needs to be explained clearly and sympathetically. Counselling has to address how pregnancy may affect not just the mother but also the fetus and the rest of the family (box 1). This allows women to make an informed choice whether they wish to accept the risks associated with pregnancy. The counselling should ideally be provided in a joint clinic by an obstetrician with expertise in heart disease and a cardiologist with special training in adult congenital heart disease. ### The risk for the mother The risk for pregnant women …

Reference values for exercise limitations among adults with congenital heart disease. Relation to activities of daily life—single centre experience and review of published data

AIMS We aimed to investigate the distribution of exercise capacity across the spectrum of adult congenital heart disease (ACHD) using own data and the published experience and to provide diagnosis, gender-, and age- specific reference values. METHODS AND RESULTS Publications describing exercise capacity in ACHD patients using cardiopulmonary exercise testing (CPET) were identified (n = 2286 patients in 23 papers). In addition, we included 2129 patients who underwent CPET at our own institution. The majority of patients (80%) had reduced peak oxygen uptake (peak VO(2)) compared with normal values (defined as <90% of predicted peak VO(2)). There were significant differences in peak VO(2) between subgroups of patients, with the lowest values seen in patients with Eisenmenger syndrome and complex heart disease. However, even in patients with simple lesions, peak VO(2) was on average significantly reduced compared with normal values. Based on a large number of observations we herewith provide gender- and age-specific peak VO(2) centile plots for the most common lesions (Tetralogy of Fallot, systemic right ventricle, Ebstein anomaly and Fontan-palliation) and relate disease-specific exercise capacity to that required for specific activities of daily life, sports, and occupations. CONCLUSION We provide age-, gender-, and diagnosis-specific data on peak VO(2) levels across the spectrum of ACHD allowing to compare the exercise capacity of individual patients with that of their peer patients. These data should be helpful in interpreting CPET results, guiding therapy, and advising patients on activities of daily life, sports participation, and choice of occupation.

Left Ventricular Longitudinal Function Predicts Life-Threatening Ventricular Arrhythmia and Death in Adults With Repaired Tetralogy of Fallot

Background— Sudden cardiac death and life-threatening ventricular arrhythmia remain a concern in adult patients with repaired tetralogy of Fallot. Longitudinal left ventricular (LV) function is sensitive in detecting early myocardial damage and may have prognostic implications in this setting. Methods and Results— We included 413 tetralogy of Fallot patients (age, 36±13 years; QRS duration, 148±27 milliseconds; LV ejection fraction, 55±10%). A composite end point of sudden cardiac death/life-threatening ventricular arrhythmia (sustained ventricular tachycardia, resuscitated sudden cardiac death, or appropriate implantable cardioverter-defibrillator discharge) was used. During a median follow-up of 2.9 years, 5 patients died suddenly, 9 had documented sustained ventricular tachycardia, and another 5 had appropriate implantable cardioverter-defibrillator shocks. On univariate Cox analysis, QRS duration (hazard ratio [HR], 1.02 per 1 ms; P=0.046), right atrial area (HR, 1.05 per 1 cm2; P=0.02), right ventricular fractional area change (HR, 0.94 per 1%; P=0.02), right ventricular outflow tract diameter (HR, 1.08 per 1 mm; P=0.01), mitral annular plane systolic excursion (HR, 0.84 per 1 mm; P=0.03), and LV global longitudinal 2-dimensional strain (HR, 0.87 per 1%; P=0.03) were related to the combined end point. On bivariable analysis, mitral annular plane systolic excursion and LV global longitudinal 2-dimensional strain were related to outcome independently of QRS duration (P=0.002 and P=0.01, respectively). In addition, a combination of echocardiographic variables, including right atrial area, right ventricular fractional area change, and LV global longitudinal 2-dimensional strain or mitral annular plane systolic excursion, was also found to be significantly related to outcome (P<0.001; c statistic, 0.70). Conclusions— LV longitudinal dysfunction was associated with greater risk of sudden cardiac death/life-threatening ventricular arrhythmias. In combination with echocardiographic right heart variables, also available from routine echocardiography, these measures provide important outcome information and should be considered a useful adjunct to established markers such as QRS duration in the estimation of prognosis in this challenging population.

Survival Prospects and Circumstances of Death in Contemporary Adult Congenital Heart Disease Patients Under Follow-Up at a Large Tertiary Centre

Background— Adult congenital heart disease (ACHD) patients have ongoing morbidity and reduced long-term survival. Recently, the importance of specialized follow-up at tertiary ACHD centers has been highlighted. We aimed to assess survival prospects and clarify causes of death in a large cohort of patients at a single, tertiary center. Methods and Results— We included 6969 adult patients (age 29.9±15.4 years) under follow-up at our institution between 1991 and 2013. Causes of death were ascertained from official death certificates. Survival was compared with the expected survival in the general age- and sex-matched population, and standardized mortality rates were calculated. Over a median follow-up time of 9.1 years (interquartile range, 5.2–14.5), 524 patients died. Leading causes of death were chronic heart failure (42%), pneumonia (10%), sudden-cardiac death (7%), cancer (6%), and hemorrhage (5%), whereas perioperative mortality was comparatively low. Isolated simple defects exhibited mortality rates similar to those in the general population, whereas patients with Eisenmenger syndrome, complex congenital heart disease, and Fontan physiology had much poorer long-term survival (P<0.0001 for all). The probability of cardiac death decreased with increasing patient’s age, whereas the proportion of patients dying from noncardiac causes, such as cancer, increased. Conclusions— ACHD patients continue to be afflicted by increased mortality in comparision with the general population as they grow older. Highest mortality rates were observed among patients with complex ACHD, Fontan physiology, and Eisenmenger syndrome. Our data provide an overview over causes of mortality and especially the spectrum of noncardiac causes of death in contemporary ACHD patients.

Right Ventricular Mechanics and QRS Duration in Patients With Repaired Tetralogy of Fallot: Implications of Infundibular Disease

Background— Patients after repair of tetralogy of Fallot (ToF) frequently have right ventricular (RV) dysfunction and prolonged QRS duration (QRSd) and thus could be candidates for cardiac resynchronization therapy. We aimed to assess the relationship between QRSd and the timing of RV wall motion, including the RV outflow tract (RVOT), in these patients. Methods and Results— Sixty-seven repaired ToF patients (median age, 34 years; interquartile range, 24 to 43 years) and 35 age-matched control subjects were studied by echocardiography and cardiovascular magnetic resonance (n=55 of 67 ToF patients). Time intervals of the RV cardiac cycle were measured from Doppler recordings. Long-axis M-mode recordings were acquired from the right ventricular (RV) free wall and RV outflow tract (RVOT), and the delay in onset of long-axis shortening was measured. ToF patients showed minor abnormalities of the RV cardiac cycle unrelated to QRSd. RV ejection time was prolonged and correspondingly filling time was reduced compared with control subjects (22.3±2.6 versus 20.0±2.9 s/min, P<0.0001; 29.0±3.8 versus 32.7±3.5 s/min, P<0.0001). Total isovolumic time was normal in ToF patients (8.7±4.0 versus 7.4±2.9 s/min; P=NS). QRSd correlated with the delay in RV free wall motion (r=0.55, P<0.0001) and more so with the delay in RVOT shortening (r=0.82, P<0.0001). QRSd also correlated with measures of RVOT abnormality such as long-axis RVOT excursion and akinetic area length (r=−0.46, P=0.004; r=0.33, P=0.01). Conclusions— QRSd in postoperative ToF patients reflects mainly abnormalities of the RVOT rather than the RV body itself. Thus, prevention and treatment of mechanical asynchrony and malignant arrhythmia should focus on the RV infundibulum. Indications for cardiac resynchronization therapy after ToF repair warrant further investigation.

Outcome of the Norwood operation in patients with hypoplastic left heart syndrome: a 12-year single-center survey.

OBJECTIVE Recent advances in perioperative care have led to a decrease in mortality of children with hypoplastic left heart syndrome undergoing the Norwood operation. This study aimed to evaluate the outcome of the Norwood operation in a single center over 12 years and to identify clinical and anatomic risk factors for adverse early and longer term outcome. METHODS Full data on all 157 patients treated between 1996 and 2007 were analyzed. RESULTS Thirty-day mortality of the Norwood operation decreased from 21% in the first 3 years to 2.5% in the last 3 years. The estimated exponentially weighted moving average of early mortality after 157 Norwood operations was 2.3%. Risk factors were an aberrant right subclavian artery, the use and duration of circulatory arrest, and the duration of total support time. The anatomic subgroup mitral stenosis/aortic atresia and female gender tended to show an increased early mortality. In the group of patients who required postoperative cardiopulmonary resuscitation, the ascending aorta was significantly smaller than in the remainder (3.03 +/- 1.05 vs 3.63 +/- 1.41 mm). Interstage mortality was 15% until the initiation of a home surveillance program in 2005, which has zeroed it so far. It was significantly higher in the mitral stenosis/aortic atresia subgroup and tended to be higher in patients who required cardiopulmonary resuscitation after the Norwood operation. The best actuarial survival was observed in the mitral atresia/aortic atresia subgroup. CONCLUSION The Norwood operation can now be performed with low mortality. Patients with mitral stenosis/aortic atresia still constitute the most challenging subgroup.

Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality

AIMS The population of adults with congenital heart disease (ACHD) is growing and ageing. Limited information about the diagnostic spectrum of this emerging population, its resource utilization at tertiary ACHD centres, and especially about prognostic parameters is available. METHODS AND RESULTS Retrospective cohort study on all ACHD patients ≥60 years of age under active follow-up. All-cause mortality was the primary outcome measure. Out of a total population of 7315 ACHD patients, 375 [190 females (50.7%), mean age 64.8 ± 5.9 years] fulfilled the inclusion criteria. During a median follow-up of 5.5 (IQR 3.1-8.6) years, 55 of the 375 patients died. The number of interventions (P = 0.0006), the number and length of hospitalization (P < 0.0001), and the number of outpatient clinic visits (P < 0.0001) were significantly higher in patients ≥60 compared with patients aged between 20 and 60 years. Patients ≥60 years of age with moderate or severe congenital heart defects had worse survival prospects than their age- and gender-matched comparison population. On multivariate Cox analysis, coronary artery disease [hazard ratio (HR): 5.04; 95%CI: 1.88-13.51, P = 0.0014], symptoms of heart failure (HR: 2.36; 95%CI: 1.05-5.29, P < 0.05), NYHA class (HR: 1.96; 95%CI: 1.18-3.26, P < 0.01), and moderate to severe reduction in systemic ventricular systolic function (HR: 1.90; 95%CI: 1.20-2.99, P < 0.001) were the strongest prognostic factors. CONCLUSION There is a growing number of elderly ACHD patients with high mortality rates and a higher utilization of healthcare resources compared with younger patients. Acquired morbidities, such as coronary artery disease, seem to be key determinants of outcome in this older population in conjunction with the underlying congenital heart disease.

Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease

Objective: To examine long-term safety and efficacy of bosentan—an oral dual endothelin receptor antagonist—in patients with pulmonary hypertension associated with congenital heart disease or Eisenmenger’s syndrome. Design: Retrospective study. Setting: Tertiary cardiology referral centre. Patients: All adult patients with pulmonary arterial hypertension associated with congenital heart disease treated with bosentan at the Royal Brompton Adult Congenital Heart Centre were included. Main outcome measures: Oxygen saturation, functional (WHO) class, 6-minute walk test distance and liver enzymes were analysed. Results: Eighteen patients (14 female) with pulmonary arterial hypertension associated with congenital heart disease (15 patients with Eisenmenger’s syndrome) with a mean (SD) age of 41 (9) years (range 23–69) were included. Median follow-up was 29 months (range 1–39). One patient died during follow-up. Patients tolerated bosentan well and no significant rise in liver transaminases was seen. Arterial oxygen saturation remained stable throughout follow-up. Mean (SD) functional class (p = 0.001) and the 6-minute walk test distance improved compared with baseline (284 (144) vs 363 (124) m, 380 (91) m and 408 (114) m at baseline, 0–6 months, 6–12 months and 1–2 years of treatment, respectively; p<0.05 for each). Conclusions: Bosentan appears to be safe and well tolerated in adults with pulmonary arterial hypertension associated with congenital heart disease or Eisenmenger’s syndrome during mid- to long-term follow-up. In addition, functional class and the 6-minute walk test distance improved and this effect was maintained for up to 2 years of bosentan treatment.

B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients: predictive value and response to disease targeting therapy

Objective To assess the relationship between elevated levels of B-type natriuretic peptide (BNP) and outcome in patients with Eisenmenger syndrome. Design Retrospective study. Setting Tertiary centre for adult congenital heart disease. Patients All patients with Eisenmenger syndrome (n=181, age 36.9±12.1 years, 31% with Down syndrome) in whom BNP concentrations were measured as part of routine clinical care were included. Main outcome measures The study end point was all cause mortality. Results During a median follow-up period of 3.3 years, 20 patients (7 with Down syndrome) died. Higher BNP concentrations were predictive of all cause mortality on univariate analysis in patients with or without Down syndrome. On multivariable Cox proportional hazard analysis, BNP predicted survival independently of renal function, Down syndrome, or 6 min walk test distance (p=0.004). Temporal increases in BNP concentration were also found to predict mortality. Treatment with disease targeting therapies was associated with a significant reduction in BNP concentrations. Conclusions BNP concentrations predict outcome in contemporary Eisenmenger patients. Increases in BNP concentrations over time are also of prognostic significance. In addition, disease targeting therapies may help to reduce BNP concentrations in this population, while treatment-naïve patients have static or rising BNP concentrations.