Annemien E. van den Bosch

The usefulness of brain natriuretic peptide in complex congenital heart disease: A systematic review

Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are well-established markers for heart failure in the general population. However, the value of BNP as a diagnostic and prognostic marker for patients with structural congenital heart disease (CHD) is still unclear. Therefore, the purpose of this study was to evaluate the clinical utility of BNP in patients with CHD. We executed a PubMed literature search and included 49 articles that focused on complex congenital heart defects such as tetralogy of Fallot, systemic right ventricle, and univentricular hearts. Data on BNP measurements and cardiac function parameters were extracted. In all patients after correction for tetralogy of Fallot, BNP levels were elevated and correlated significantly with right ventricular end-diastolic dimensions and severity of pulmonary valve regurgitation. Patients with a systemic right ventricle had elevated BNP levels, and positive correlations between BNP and right ventricular function were seen. In patients with a univentricular heart, elevated BNP levels were observed before completion of the Fontan circulation or when patients were symptomatic; a clear association between BNP and New York Heart Association functional class was demonstrated. In conclusion, this review shows an overall increase in BNP values in complex CHD, although differences between types of congenital heart anomaly are present. As BNP values differ widely, conclusions for individual patients should be drawn with caution. Further investigation with sequential BNP measurement in a large, prospective study is warranted to elucidate the prognostic value of BNP assessment in patients with CHD.

The natural and unnatural history of the Mustard procedure: long-term outcome up to 40 years

AIMS To describe long-term survival, clinical outcome and ventricular systolic function in a longitudinally followed cohort of patients after Mustard repair for transposition of the great arteries (TGA). There is serious concern about the long-term outcome after Mustard repair. METHODS AND RESULTS This longitudinal single-centre study consisted of 91 consecutive patients, who underwent Mustard repair before 1980, at age <15 years, and were evaluated in-hospital every 10 years. Survival status was obtained of 86 patients. Median follow-up was 35 (IQR 34-38) years. Cumulative survival was 84% after 10 years, 80% after 20 years, 77% after 30 years, and 68% after 39 years. Cumulative survival free of events (i.e. heart transplantation, arrhythmias, reintervention, and heart failure) was 19% after 39 years. Reinterventions were mainly required for baffle-related problems. Supraventricular and ventricular arrhythmias occurred in 28 and 6% of the patients, respectively. Pacemaker and/or ICD implantation was performed in 39%. Fifty survivors participated in the current in-hospital investigation including electrocardiography, 2D-echocardiography, cardiopulmonary-exercise testing, NT-proBNP measurement, Holter monitoring, and cardiac magnetic resonance. Right ventricular systolic function was impaired in all but one patient at last follow-up, and 14% developed heart failure in the last decade. NT-proBNP levels [median 31.6 (IQR 22.3-53.2) pmol/L] were elevated in 92% of the patients. Early postoperative arrhythmias were a predictor for late arrhythmias [HR 3.8 (95% CI 1.5-9.5)], and development of heart failure [HR 8.1 (95% CI 2.2-30.7)]. Also older age at operation was a predictor for heart failure [HR 1.26 (95% CI 1.0-1.6)]. CONCLUSION Long-term survival after Mustard repair is clearly diminished and morbidity is substantial. Early postoperative arrhythmias are a predictor for heart failure and late arrhythmias.

Unnatural history of tetralogy of fallot: Prospective follow-up of 40 years after surgical correction

Background— Prospective data on long-term survival and clinical outcome beyond 30 years after surgical correction of tetralogy of Fallot are nonexistent. Methods and Results— This longitudinal cohort study consists of the 144 patients with tetralogy of Fallot who underwent surgical repair at <15 years of age between 1968 and 1980 in our center. They are investigated every 10 years. Cumulative survival (data available for 136 patients) was 72% after 40 years. Late mortality was due to heart failure and ventricular fibrillation. Seventy-two of 80 eligible survivors (90%) participated in the third in-hospital investigation, consisting of ECG, Holter, echocardiography, cardiopulmonary exercise testing, N-terminal pro-brain natriuretic peptide measurement, cardiac magnetic resonance (including dobutamine stress testing), and the Short Form-36 questionnaire. Median follow-up was 36 years (range, 31–43 years). Cumulative event-free survival was 25% after 40 years. Subjective health status was comparable to that in the normal Dutch population. Although systolic right and left ventricular function declined, peak exercise capacity remained stable. There was no progression of aortic root dilation. A previous shunt operation, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality (hazard ratio, 2.9, 1.1, and 2.5, respectively). An increase in QRS duration and a deterioration of exercise tolerance and ventricular dysfunction did not predict mortality. Insertion of a transannular patch was a predictor for late arrhythmias (hazard ratio, 4.0; 95% confidence interval, 1.2–13.4). Conclusions— Although many patients needed a reoperation or developed arrhythmias, late mortality was low, and the clinical condition and subjective health status of most patients remained good. Previous shunt, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality. # CLINICAL PERSPECTIVE {#article-title-36}Background— Prospective data on long-term survival and clinical outcome beyond 30 years after surgical correction of tetralogy of Fallot are nonexistent. Methods and Results— This longitudinal cohort study consists of the 144 patients with tetralogy of Fallot who underwent surgical repair at <15 years of age between 1968 and 1980 in our center. They are investigated every 10 years. Cumulative survival (data available for 136 patients) was 72% after 40 years. Late mortality was due to heart failure and ventricular fibrillation. Seventy-two of 80 eligible survivors (90%) participated in the third in-hospital investigation, consisting of ECG, Holter, echocardiography, cardiopulmonary exercise testing, N-terminal pro-brain natriuretic peptide measurement, cardiac magnetic resonance (including dobutamine stress testing), and the Short Form-36 questionnaire. Median follow-up was 36 years (range, 31–43 years). Cumulative event-free survival was 25% after 40 years. Subjective health status was comparable to that in the normal Dutch population. Although systolic right and left ventricular function declined, peak exercise capacity remained stable. There was no progression of aortic root dilation. A previous shunt operation, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality (hazard ratio, 2.9, 1.1, and 2.5, respectively). An increase in QRS duration and a deterioration of exercise tolerance and ventricular dysfunction did not predict mortality. Insertion of a transannular patch was a predictor for late arrhythmias (hazard ratio, 4.0; 95% confidence interval, 1.2–13.4). Conclusions— Although many patients needed a reoperation or developed arrhythmias, late mortality was low, and the clinical condition and subjective health status of most patients remained good. Previous shunt, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality.

The unnatural history of an atrial septal defect: Longitudinal 35 year follow up after surgical closure at young age

Objective To describe the very long-term outcome after surgical closure of an atrial septal defect (ASD). Design Longitudinal cohort study of 135 consecutive patients who underwent surgical ASD repair at age <15 years between 1968 and 1980. The study protocol included ECG, echocardiography, exercise testing, N-terminal prohormone of brain natriuretic hormone, Holter monitoring and cardiac MRI. Main outcome measures Survival, major events (cardiac reinterventions, stroke, symptomatic arrhythmia or heart failure) and ventricular function. Results After 35 years (range 30–41), survival status was obtained in 131 of 135 patients (97%): five died (4%), including two sudden deaths in the last decade. Fourteen patients (16%) had symptomatic supraventricular tachyarrhythmias and six (6%) had a pacemaker implanted which was predicted by early postoperative arrhythmias. Two reoperations were performed. One ischaemic stroke occurred. Left ventricular (LV) and right ventricular (RV) ejection fractions (EF) were 58±7% and 51±6%, respectively. RVEF was diminished in 17 patients (31%) and in 11 (20%) the RV was dilated. Exercise capacity and quality of life were comparable to the normal population. No clear differences were found between ASD-II or sinus venosus type ASD. Conclusions Very long-term outcome after surgical ASD closure in childhood shows good survival and low morbidity. Early surgical closure prevents pulmonary hypertension and reduces the occurrence of supraventricular arrhythmias. Early postoperative arrhythmias are predictive for the need for pacemaker implantation during early follow-up, but the rate of late pacemaker implantation remains low. Although RVEF was unexpectedly found to be decreased in one-third of patients, the functional status remains excellent.

The unnatural history of the ventricular septal defect: Outcome up to 40 years after surgical closure

BACKGROUND Few prospective data are available regarding long-term outcomes after surgical closure of a ventricular septal defect (VSD). OBJECTIVES The objective of this study was to investigate clinical outcomes>30 years after surgical VSD closure. METHODS Patients who underwent surgical VSD closure during childhood between 1968 and 1980 were reexamined every 10 years. In 2012, we invited eligible patients to undergo another examination, which included electrocardiography, Holter monitoring, echocardiography, bicycle ergometry, measurement of N-terminal pro-B-type natriuretic peptide, and subjective health assessment. RESULTS Cumulative survival was 86% at 40 years. Causes of mortality were arrhythmia, heart failure, endocarditis, during valvular surgery, pulmonary hypertension, noncardiac causes, and unknown causes. Cumulative event-free survival after surgery was 72% at 40 years. Symptomatic arrhythmias occurred in 13% of patients and surgical or catheter-based reinterventions in 12%. Prevalence of impaired right ventricular systolic function increased from 1% in 2001 to 17% in 2012 (p=0.001). Left ventricular systolic function was impaired but stable in 21% of patients. Aortic regurgitation occurred more often in the last 20 years (p=0.039), and mean exercise capacity decreased (p=0.003). N-terminal pro-B-type natriuretic peptide (median: 11.6 pmol/l [interquartile range: 7.0 to 19.8 pmol/l]) was elevated (>14 pmol/l) in 38% of patients. A concomitant cardiac lesion, for example, patent ductus arteriosus, and aortic cross-clamp time were determinants of late events (hazard ratio: 2.84 [95% confidence interval: 1.23 to 6.53] and hazard ratio: 1.47 per 10 min [95% confidence interval: 1.22 to 1.99], respectively). Patients rated their subjective health status significantly better than a reference population. CONCLUSIONS Survival up to 40 years after successful surgical VSD closure is slightly lower than in the general Dutch population. Morbidity is not negligible, especially in patients with a concomitant cardiac lesion.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Adult Congenital Heart Disease

Background: The number of patients with adult congenital heart disease (ACHD) is rapidly increasing. To optimize patient management, there is a great need to accurately identify high-risk patients. Still, no biomarker has been firmly established as a clinically useful prognostic tool in this group. We studied the association of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitive troponin-T, and growth-differentiation factor 15 with cardiovascular events in ACHD. Methods: Clinically stable patients with ACHD who routinely visited the outpatient clinic between April 2011 and April 2013 underwent clinical assessment, electrocardiography, echocardiography, and biomarker measurement (NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15) at the time of study inclusion. Patients were prospectively followed for the occurrence of cardiovascular events (death, heart failure, hospitalization, arrhythmia, thromboembolic events, and reintervention). Survival curves were derived by the Kaplan-Meier method, and Cox regression was performed to investigate the relation between biomarkers and events with adjustment for multiple clinical and echocardiographic variables. Results: In total, 595 patients were included (median age, 33 years; interquartile range, 25–41 years; 58% male; 90% New York Heart Association class I). Patients were followed during a median of 42 (interquartile range, 37–46) months. Of the 3 evaluated biomarkers, NT-proBNP in the upper quartile (>33.3 pmol/L) was most strongly associated with cardiovascular events (n=165, adjusted hazard ratio, 9.05 [3.24–25.3], P<0.001) and with death or heart failure (n=50, adjusted hazard ratio, 16.0 [2.04–126], P<0.001). When NT-proBNP was analyzed as a continuous variable, similar findings were retrieved. The cumulative proportion of patients with death and heart failure was only 1% in the lowest 2 NT-proBNP quartiles. Elevated NT-proBNP (>14 pmol/L), elevated high-sensitive troponin-T (>14 ng/L), and elevated growth-differentiation factor 15 (>1109 ng/L) identified those patients at highest risk of cardiovascular events (log-rank P<0.0001). Conclusions: NT-proBNP provides prognostic information beyond a conventional risk marker model in patients with ACHD and can reliably exclude the risk of death and heart failure. Elevated levels of NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15 identify patients at highest risk of cardiovascular events. These biomarkers therefore may play an important role in the monitoring and management of patients with ACHD.

Abnormal left ventricular rotation and twist in adult patients with corrected tetralogy of Fallot

AIMS Left ventricular (LV) dysfunction is a major determinant of late adverse clinical outcome in adult patients with tetralogy of Fallot (ToF). Therefore, early detection is important. Speckle-tracking echocardiography (STE) has emerged as a quantitative technique to assess LV function. The aim of this study was to evaluate LV rotation and twist with STE in adult ToF patients and their association with right ventricular (RV) and LV dimensions and function, exercise capacity, and NT-proBNP level. METHODS Eighty-two ToF patients and 56 healthy controls matched for age and gender underwent echocardiography, electrocardiography, cardiac magnetic resonance imaging (CMR), bicycle ergometry, and NT-proBNP measurement. For STE, short-axis parasternal views were obtained at the LV base and apex. We analysed LV apical and basal rotation curves and calculated LV twist. RESULTS Of the 82 ToF patients (55% male, age 33 ± 10 years, 98% NYHA I), 58 (71%) had normal twist, but lower than the controls [12.5 (IQR: 6.6) vs. 16.9 (IQR: 8.2) degrees, P = 0.002] mainly due to decreased apical rotation. Twenty-one (26%) patients had abnormal apical rotation which was associated with larger LV dimensions and decreased systolic biventricular function. Multivariable regression analyses showed positive relations of LV twist with biventricular systolic function measured with echocardiography as well as CMR. CONCLUSION The majority of adults with corrected ToF show a reduced LV twist. Strikingly, one-quarter of these patients have an abnormal apical rotation which is associated with decreased systolic LV and RV function. These findings suggest that abnormal apical rotation is a new objective diagnostic criterion for detection of ventricular dysfunction.

Progression rate and early surgical experience in the new aggressive aneurysms-osteoarthritis syndrome.

BACKGROUND Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant condition characterized by aneurysms throughout the arterial tree in combination with osteoarthritis. The objective of the present study was to evaluate progression rate of aortic dilation and surgical outcome in AOS patients. METHODS All AOS patients are regularly monitored according to our clinical AOS protocol. Patients with at least two follow-up visits or who underwent aortic root surgery during follow-up were included in this cohort study. Clinical and surgical data were obtained from chart abstraction. RESULTS We included 22 patients (aged 38 ± 15 years; 41% male) with the molecular diagnosis of AOS. Follow-up duration was 3.3 years (interquartile range, 1.6 to 5.1). In the 17 patients who were managed conservatively, aortic root diameter increased from 37.5 ± 5.1 mm at baseline to 40.3 ± 6.2 mm at follow-up (p = 0.008). Progression rate of aortic dilation was highest at the level of the sinus of Valsalva (2.5 ± 5.8 mm per year) and significantly correlated with the initial diameter (r = 0.603, p = 0.017). Ten patients successfully underwent valve-sparing aortic root replacement, 5 after previous watchful waiting. Mean preoperative aortic diameter was 46.6 ± 4.0 mm. The operations were not complicated by fragility of tissue. After a postoperative period of 2.8 years (interquartile range, 0.7 to 5.4), no mortality or reoperations had occurred, and all patients remained asymptomatic. CONCLUSIONS Aneurysm growth in AOS patients can be fast and unpredictable, warranting extensive and frequent cardiovascular monitoring. Valve-sparing aortic root replacement is a safe and effective procedure for the management of aortic root aneurysms in AOS patients.

Assessment of ventricular function in adults with repaired Tetralogy of Fallot using myocardial deformation imaging

AIMS Many patients with repaired Tetralogy of Fallot (ToF) have right ventricular (RV) volume overload due to pulmonary regurgitation (PR). We studied the effect of volume overload on global and regional RV and left ventricular (LV) deformation, and their relationships with conventional diagnostic parameters. METHODS AND RESULTS In this cross-sectional study, 94 prospectively recruited ToF patients (61% male, age 32.8 ± 9.5 years, age at repair 1.9 [0.8-5.7] years, 39% pulmonary homograft) and 85 healthy controls of similar age and sex underwent echocardiography and electrocardiography. In a subset of patients, cardiac magnetic resonance imaging, bicycle ergometry, and NT-proBNP measurement were performed within the same day. With speckle-tracking echocardiography, we analysed peak systolic global longitudinal strain (GLS), segmental longitudinal strain and strain rate of the RV free wall, LV lateral wall, and septum. Patients had a lower RV free wall strain than controls (-18.1 ± 4.5 vs. -26.5 ± 4.5%, P < 0.001), especially at the apical segment (-15.9 ± 7.4 vs. -28.2 ± 7.7%, P < 0.001), and lower RV strain rate. LV GLS was also lower (-17.4 ± 2.5 vs. -19.6 ± 1.9%, P < 0.001), mainly due to the interventricular septum. Patients with PR >25% had higher LV GLS and RV free wall strain than patients with PR ≤25% (P = 0.004, P = 0.039, respectively). No relationships were found with NT-proBNP or exercise capacity. CONCLUSION RV free wall strain and strain rate are decreased in adults late after ToF repair, especially at the apical segment suggesting that apical function is most affected in these RVs. Regarding the LV, septal strain is decreased indicating that RV dysfunction adversely affects LV function, probably by mechanical coupling of the ventricles.

High-sensitive troponin-T in adult congenital heart disease☆☆☆

BACKGROUND Adult congenital heart disease (ACHD) patients are at risk of late complications including arrhythmias, heart failure and sudden death. High-sensitive troponin-T (hs-TnT) is the standard for diagnosing acute coronary syndrome, but is also associated with cardiac function and prognosis in other cardiac diseases. We aimed to describe hs-TnT level in ACHD patients, and determine its relationship with cardiac function and other biomarkers. METHODS Consecutive ACHD patients, visiting the outpatient clinic, underwent echocardiography, exercise testing and venipuncture on the same day. RESULTS In total 587 patients were included (median age 33 [IQR 25-41] years, 58% male, 90% NYHA class I). hs-TnT was above the detection limit of 5 ng/L in 241 patients (41%), of whom 47 (8%) had hs-TnT levels above the 99th percentile of normal of 14 ng/L. hs-TnT levels were highest in patients with a systemic RV or pulmonary hypertension. Patients with normal or non-detectable hs-TnT were younger (32 [IQR 24-40] years) than patient with elevated hs-TnT (42 [IQR 36-60] years, p<0.001). The prevalence of hs-TnT ≥14 ng/L was higher in patients with NYHA ≥II (36%, p<0.001), systemic systolic dysfunction (38%, p<0.001), non-sinus rhythm (43%, p<0.001) and elevated pulmonary pressures (39%, p<0.001). hs-TnT was correlated with NT-proBNP (r=0.400, p<0.001). CONCLUSIONS hs-TnT above the 99th percentile of normal is observed in a non-trivial portion of stable ACHD patients, especially in those with a systemic RV or elevated pulmonary pressures. Since this biomarker of myocardial damage is related to NT-proBNP and ventricular function, its potential predictive value in ACHD patients seems promising and further investigation of underlying mechanisms is warranted.