Gerhard-Paul Diller

Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication.

Background—Although some patients with adult congenital heart disease (ACHD) report limitations in exercise capacity, we hypothesized that depressed exercise capacity may be more widespread than superficially evident during clinical consultation and could be a means of assessing risk. Methods and Results—Cardiopulmonary exercise testing was performed in 335 consecutive ACHD patients (age, 33±13 years), 40 non–congenital heart failure patients (age, 58±15 years), and 11 young (age, 29±5 years) and 12 older (age, 59±9 years) healthy subjects. Peak oxygen consumption (peak &OV0312;o2) was reduced in ACHD patients compared with healthy subjects of similar age (21.7±8.5 versus 45.1±8.6; P<0.001). No significant difference in peak &OV0312;o2 was found between ACHD and heart failure patients of corresponding NYHA class (P=NS for each NYHA class). Within ACHD subgroups, peak &OV0312;o2 gradually declined from aortic coarctation (28.7±10.4) to Eisenmenger (11.5±3.6) patients (P<0.001). Multivariable correlates of peak &OV0312;o2 were peak heart rate (r=0.33), forced expiratory volume (r=0.33), pulmonary hypertension (r=−0.26), gender (r=−0.23), and body mass index (r=−0.19). After a median follow-up of 10 months, 62 patients (18.5%) were hospitalized or had died. On multivariable Cox analysis, peak &OV0312;o2 predicted hospitalization or death (hazard ratio, 0.937; P=0.01) and was related to the frequency and duration of hospitalization (P=0.01 for each). Conclusions—Exercise capacity is depressed in ACHD patients (even in allegedly asymptomatic patients) on a par with chronic heart failure subjects. Lack of heart rate response to exercise, pulmonary arterial hypertension, and impaired pulmonary function are important correlates of exercise capacity, as is underlying cardiac anatomy. Poor exercise capacity identifies ACHD patients at risk for hospitalization or death.

Pulmonary Vascular Disease in Adults With Congenital Heart Disease

Pulmonary arterial hypertension of variable degree is commonly associated with adult congenital heart disease. Depending on size and location of the underlying cardiac defect as well as on repair status, pulmonary arterial hypertension may present with or without reversed shunting and associated cyanosis (ie, Eisenmenger syndrome). We review available data on etiology, clinical presentation, prognosis, and management strategies of pulmonary arterial hypertension in adult patients with congenital heart disease. In addition, we discuss the numerous complications associated with Eisenmenger syndrome, representing a multisystem disorder. Finally, we present general management strategies and emerging disease-targeting therapies.

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.

Prevalence, Predictors, and Prognostic Value of Renal Dysfunction in Adults With Congenital Heart Disease

Background— Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. Methods and Results— A total of 1102 adult patients with congenital heart disease (age 36.0±14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (≥90 mL · min−1 · 1.73 m−2), mildly impaired GFR (60 to 89 mL · min−1 · 1.73 m−2), and moderately/severely impaired GFR (<60 mL · min−1 · 1.73 m−2). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL · min−1 · 1.73 m−2, P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). Conclusions— Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients

AIMS previous studies have established an association between exercise intolerance and increased morbidity and mortality in congenital heart disease patients. We aimed to clarify if exercise intolerance is associated with poor outcome in Fontan patients and to identify risk factors for mortality, transplantation, and cardiac-related hospitalization. METHODS AND RESULTS a total of 321 Fontan patients (57% male, mean age 20.9 ± 8.6 years) who underwent cardiopulmonary exercise testing (CPET) at four major European centres between 1997 and 2008 were included. During a median follow-up of 21 months, 22 patients died and 6 patients underwent cardiac transplantation (8.7%), resulting in an estimated 5-year transplant-free survival of 86%. Parameters of CPET were strongly related to increased risk of hospitalization, but-with the exception of heart rate reserve-unrelated to risk of death or transplantation. In contrast, patients with clinically relevant arrhythmia had a 6.0-fold increased risk of death or transplantation (P < 0.001). Furthermore, patients with atriopulmonary/-ventricular Fontan had a 3.7-fold increased risk of death or transplantation compared with total cavopulmonary connection patients (P= 0.009). The combination of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and signs of symptomatic or decompensated heart failure was associated with a particularly poor outcome (3-year mortality 25%). CONCLUSION on short-term follow-up, most parameters of CPET are associated with increased risk of hospitalization but not death or transplantation in contemporary Fontan patients. Only decreased heart rate reserve and a history of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and/or heart failure requiring diuretic therapy are associated with poor prognosis, potentially identifying patients requiring medical and/or surgical attention.

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.

Comprehensive Use of Cardiopulmonary Exercise Testing Identifies Adults With Congenital Heart Disease at Increased Mortality Risk in the Medium Term

Background— Parameters of cardiopulmonary exercise testing were recently identified as strong predictors of mortality in adults with congenital heart disease. We hypothesized that combinations of cardiopulmonary exercise testing parameters may provide optimal prognostic information on midterm survival in this population. Methods and Results— A total of 1375 consecutive adult patients with congenital heart disease (age, 33±13 years) underwent cardiopulmonary exercise testing at a single center over a period of 10 years. Peak oxygen consumption (peak V[Combining Dot Above]O2), ventilation per unit of carbon dioxide production (V[Combining Dot Above]E/V[Combining Dot Above]CO2 slope), and heart rate reserve were measured. During a median follow-up of 5.8 years, 117 patients died. Peak V[Combining Dot Above]O2, heart rate reserve, and V[Combining Dot Above]E/V[Combining Dot Above]CO2 slope were related to midterm survival in adult patients with congenital heart disease. Risk of death increased with lower peak V[Combining Dot Above]O2 and heart rate reserve. A higher V[Combining Dot Above]E/V[Combining Dot Above]CO2 slope was also related to increased risk of death in noncyanotic patients, whereas the V[Combining Dot Above]E/V[Combining Dot Above]CO2 slope was not predictive of mortality in cyanotic patients. The combination of peak V[Combining Dot Above]O2 and heart rate reserve provided the greatest predictive information after adjustment for clinical parameters such as negative chronotropic agents, age, and presence of cyanosis. However, the incremental value of these exercise parameters was reduced in patients with peak respiratory exchange ratio <1.0. Conclusions— Cardiopulmonary exercise testing provides strong prognostic information in adult patients with congenital heart disease. Prognostication should be approached differently, depending on the presence of cyanosis, use of rate-lowering medications, and achieved level of exercise. We provide 5-year survival prospects based on cardiopulmonary exercise testing parameters in this growing population.