Two decades of aortic coarctation treatment in children; evaluating techniques.

OBJECTIVE: This study focuses on the evolution of treatment techniques for aortic coarctation in children and assesses long-term morbidity. METHODS: This retrospective cohort study evaluates patients treated for native aortic coarctation, with at least 7 years of follow-up. To assess time-related changes, three time periods were distinguished according to year of primary intervention (era 1, 2 and 3). Operative and long-term follow-up data were collected by patient record reviews. RESULTS: The study population consisted of 206 patients (177 surgical and 29 catheter-based interventions), with a median follow-up of 151 months. Anterior approach with simultaneous repair of aortic arch and associated cardiac lesions was more common in the most recent era. Median age at intervention did not change over time. Reintervention was necessary in one third of the cohort with an event-free survival of 74% at 5­year and 68% at 10-year follow-up. Reintervention rates were significantly higher after catheter-based interventions compared with surgical interventions (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.04-3.00, p = 0.04) and in patients treated before 3 months of age (HR 2.1, 95% CI 1.27-3.55, p = 0.003). Hypertension was present in one out of five patients. CONCLUSION: Nowadays, complex patients with associated cardiac defects and arch hypoplasia are being treated surgically on bypass, whereas catheter-based intervention is introduced for non-complex patients. Reintervention is common and more frequent after catheter-based intervention and in surgery under 3 months of age. One fifth of the 206 patients remained hypertensive.

New developments in adult congenital heart disease.

Congenital heart disease (CHD) affects 0.8% of live births and over the past decades technical improvements and large-scale repair has led to increased survival into adulthood of over 95% of the new-born. A new group of patients, those who survived their congenital heart defect, has emerged but late complications including heart failure, pulmonary hypertension (PH), arrhythmias, aneurysms and endocarditis appeared numerous, with a huge impact on mortality and morbidity. However, innovations over the past years have changed the landscape of adult CHD dramatically. In the diagnostic process important improvements have been made in the use of MRI, biomarkers, e­health concepts and 3D visualisation of anatomy. Care is now concentrated in specialised centres, with a continuous emphasis on education and the introduction of weekly multidisciplinary consultations on diagnosis and intervention. Surgery and percutaneous intervention have been refined and new concepts applied, further reducing the burden of the congenital malformations. Research has matured from case series to global networks. Currently, adults with CHD are still facing high risks of early mortality and morbidity. By global collaboration and continuous education and development and innovation of our diagnostic and therapeutic arsenal, we will improve the perspectives of these young patients.

Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study.

BACKGROUND: Current guidelines consider vitamin K antagonists (VKA) the oral anticoagulant agents of choice in adults with atrial arrhythmias (AA) and moderate or complex forms of congenital heart disease, significant valvular lesions, or bioprosthetic valves, pending safety data on non-VKA oral anticoagulants (NOACs). Therefore, the international NOTE registry was initiated to assess safety, change in adherence and quality of life (QoL) associated with NOACs in adults with congenital heart disease (ACHD). METHODS: An international multicenter prospective study of NOACs in ACHD was established. Follow-up occurred at 6 months and yearly thereafter. Primary endpoints were thromboembolism and major bleeding. Secondary endpoints included minor bleeding, change in therapy adherence (≥80% medication refill rate, ≥6 out of 8 on Morisky-8 questionnaire) and QoL (SF-36 questionnaire). RESULTS: In total, 530 ACHD patients (mean age 47 SD 15 years; 55% male) with predominantly moderate or complex defects (85%), significant valvular lesions (46%) and/or bioprosthetic valves (11%) using NOACs (rivaroxaban 43%; apixaban 39%; dabigatran 12%; edoxaban 7%) were enrolled. The most common indication was AA (91%). Over a median follow-up of 1.0 [IQR 0.0-2.0] year, thromboembolic event rate was 1.0% [95%CI 0.4-2.0] (n = 6) per year, with 1.1% [95%CI 0.5-2.2] (n = 7) annualized rate of major bleeding and 6.3% [95%CI 4.5-8.5] (n = 37) annualized rate of minor bleeding. Adherence was sufficient during 2 years follow-up in 80-93% of patients. At 1-year follow-up, among the subset of previous VKA-users who completed the survey (n = 33), QoL improved in 6 out of 8 domains (p ≪ 0.05). CONCLUSIONS: Initial results from our worldwide prospective study suggest that NOACs are safe and may be effective for thromboembolic prevention in adults with heterogeneous forms of congenital heart disease.

Safety and efficacy of stenting for aortic arch hypoplasia in patients with coarctation of the aorta.

BACKGROUND: Despite a successful repair procedure for coarctation of the aorta (CoA), up to two-thirds of patients remain hypertensive. CoA is often seen in combination with abnormal aortic arch anatomy and morphology. This might be a substrate for persistent hypertension. Therefore, we performed endovascular aortic arch stent placement in patients with CoA and concomitant aortic arch hypoplasia or gothic arch morphology. The goal of this retrospective analysis was to investigate the safety and efficacy of aortic arch stenting. METHODS: A retrospective analysis was performed in patients who underwent stenting of the aortic arch at the University Medical Center Utrecht. Measurements collected included office blood pressure, use of antihypertensive medication, invasive peak-to-peak systolic pressure over the arch, and aortic diameters on three-dimensional angiography. Data on follow-up were obtained at the date of most recent outpatient visit. RESULTS: Twelve patients underwent stenting of the aortic arch. Mean follow-up duration was 14 ± 11 months. Mean peak-to-peak gradient across the arch decreased from 39 ± 13 mm Hg to 7 ± 8 mm Hg directly after stenting (p < 0.001). There were no major procedural complications. Mean systolic blood pressure decreased from 145 ± 16 mm Hg at baseline to 128 ± 9 mm Hg at latest follow-up (p = 0.014). CONCLUSION: This retrospective study shows that stenting of the aortic arch is successful when carried out in a state-of-the-art manner. A direct optimal angiographic and haemodynamic result was shown. No major complications occurred during or after the procedure. At short- to medium-term follow-up a decrease in mean systolic blood pressure was observed.

Maternal right ventricular function, uteroplacental circulation in first trimester and pregnancy outcome in women with congenital heart disease.

OBJECTIVE: Pregnant women with congenital heart disease (CHD) have an increased risk of abnormal uteroplacental flow, measured from the second trimester onwards, which is associated with pregnancy complications affecting the mother and the fetus. Maternal right ventricular (RV) dysfunction has been suggested as a predisposing factor for impaired uteroplacental flow in these women. The aim of this study was to investigate the association of first-trimester uteroplacental flow measurements with prepregnancy maternal cardiac function and pregnancy complications in women with CHD, with particular focus on the potential role of RV (dys)function. METHODS: This study included 138 pregnant women with CHD from the prospective ZAHARA III study (Zwangerschap bij Aangeboren HARtAfwijkingen; Pregnancy and CHD). Prepregnancy clinical and echocardiographic data were collected. Clinical evaluation, echocardiography (focused on RV function, as assessed by tricuspid annular plane systolic excursion (TAPSE)) and uterine artery (UtA) pulsatility index (PI) measurements were performed at 12, 20 and 32 weeks of gestation. Univariable and multivariable regression analyses were performed to assess the association between prepregnancy variables and UtA-PI during pregnancy. The association between UtA-PI at 12 weeks and cardiovascular, obstetric and neonatal complications was also assessed. RESULTS: On multivariable regression analysis, prepregnancy TAPSE was associated negatively with UtA-PI at 12 weeks of gestation (ß = -0.026; P = 0.036). Women with lower prepregnancy TAPSE (≤ 20 mm vs > 20 mm) had higher UtA-PI at 12 weeks (1.5 ± 0.5 vs 1.2 ± 0.6; P = 0.047). Increased UtA-PI at 12 weeks was associated with obstetric complications (P = 0.003), particularly hypertensive disorders (pregnancy-induced hypertension and pre-eclampsia, P = 0.019 and P = 0.026, respectively). CONCLUSIONS: In women with CHD, RV dysfunction before pregnancy seems to impact placentation, resulting in increased resistance in UtA flow, which is detectable as early as in the first trimester. This, in turn, is associated with pregnancy complications. Early monitoring of uteroplacental flow might be of value in women with CHD with pre-existing subclinical RV dysfunction to identify pregnancies that would benefit from close obstetric surveillance. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

NT-proBNP and exercise capacity in adult patients with congenital heart disease and a prosthetic valve: a multicentre PROSTAVA study.

OBJECTIVES: N-terminal B­type natriuretic peptide (NT-proBNP) is an important biomarker for the detection of heart failure. Adults with congenital heart disease (ACHD) and a prosthetic heart valve are at risk for heart failure. This study aimed to determine the value of NT-proBNP in ACHD patients with a prosthetic valve and investigate its relationship with cardiac function and exercise capacity. METHODS: In this multi-centre cross-sectional observational study, data regarding medical history, echocardiography, exercise testing (VO2peak) and laboratory blood evaluation (including NT-proBNP) were collected in ACHD patients with a single prosthetic valve (either homografts, heterografts or mechanical valves). RESULTS: A total of 306 ACHD patients with pulmonary valve replacement (PVR, n = 139), aortic valve replacement (n = 141), mitral valve replacement (n = 21) or tricuspid valve replacement (n = 5) were investigated. The majority of patients (77 %) were in NYHA class I or II. Elevated NT-proBNP levels (cut-off ≥125 pg/ml) were found in 50 % of the patients, with the highest levels in patients with mitral valve replacements. In this study population, NT-proBNP levels were associated with gender (p = 0.029) and VO2max (p < 0.001). In PVR patients, NT-proBNP levels were associated with lower VO2peak, also after adjustment for age, gender and age at valve replacement in a multivariate model (p = 0.015). CONCLUSIONS: In patients with ACHD and a prosthetic valve, elevated NT-proBNP levels are frequently observed despite preserved NYHA class. In PVR patients, a higher NT-proBNP level was associated with a lower VO2peak. These results may be of importance in the ongoing discussion about the timing of valve replacement in patients with CHD.

Echocardiographic findings associated with mortality ortransplant in patients with pulmonary arterial hypertension:A systematic review and meta-analysis.

BACKGROUND: Identification of patients at risk of deterioration is essential to guide clinical management in pulmonary arterial hypertension (PAH). This study aims to provide a comprehensive overview of well-investigated echocardiographic findings that are associated with clinical deterioration in PAH. METHODS: MEDLINE and EMBASE databases were systematically searched for longitudinal studies published by April 2015 that reported associations between echocardiographic findings and mortality, transplant or clinical worsening. Meta-analysis using random effect models was performed for echocardiographic findings investigated by four or more studies. In case of statistical heterogeneity a sensitivity analysis was conducted. RESULTS: Thirty-seven papers investigating 51 echocardiographic findings were included. Meta-analysis of univariable hazard ratios (HRs) and sensitivity analysis showed that presence of pericardial effusion (pooled HR 1.70; 95 % CI 1.44-1.99), right atrial area (pooled HR 1.71; 95 % CI 1.38-2.13) and tricuspid annular plane systolic excursion (TAPSE; pooled HR 1.72; 95 % CI 1.34-2.20) were the most well-investigated and robust predictors of mortality or transplant. CONCLUSIONS: This meta-analysis substantiates the clinical yield of specific echocardiographic findings in the prognostication of PAH patients in day-to-day practice. In particular, pericardial effusion, right atrial area and TAPSE are of prognostic value.

Haemodynamics in a patient with Fontan physiology undergoing laparoscopic cholecystectomy.

Laparoscopic surgery in patients with Fontan circulation is a haemodynamic challenge; venous return may be compromised by insufflation of carbon dioxide into the abdomen (increasing intra-abdominal pressure), the use of reverse Trendelenburg position and positive pressure ventilation. Combined with an increase in pulmonary vascular resistance due to hypercarbia, cardiac output may be reduced. However, for non-haemodynamic reasons, laparoscopic surgery has advantages over open surgery: less postoperative pain, shorter hospital stay, a reduction in postoperative wound infections and a reduction of respiratory complications. In this case report, we present a patient with Fontan circulation who underwent uneventful laparoscopic cholecystectomy.

Beneficial effect of high dose statins on the vascular wall in patients with repaired aortic coarctation?

BACKGROUND: Carotid intima-media thickness (CIMT) is a marker for atherosclerosis. Adult post-coarctectomy patients (CoA) demonstrate an increased cardiovascular risk and increased CIMT compared to controls. This study evaluates the effect of high dose statins on the change in CIMT and cardiovascular risk. METHODS: We designed a multicenter, prospective, randomized, open label trial with blinded endpoint (PROBE design) to evaluate the effect of three year treatment with atorvastatin 80 mg on CIMT and cardiovascular risk. Primary endpoint was CIMT measured by B mode ultrasonography. Secondary endpoints were mortality and morbidity due to cardiovascular disease and serum lipids. RESULTS: 155 patients (36.3 ± 11.8 years, 96 (62%) male) were randomized (atorvastatin=80, no treatment=75). There was no significant effect of atorvastatin on the change in CIMT (treatment effect -0.005, 95% CI, -0.039-0.029; P=0.76). A significant effect on serum cholesterol and LDL levels was found (- 0.71, 95% CI, - 1.16 to - 0.26; P = 0.002 vs - 0.66, 95% CI - 1.06 to - 0.26; P = 0.001). There was no difference in secondary outcome measures. Baseline CIMT was higher in hypertensive compared to normotensive CoA. (0.69 ± 0.16 mm vs 0.61 ± 0.98 mm; P=0.002). Hypertension (ß=0.043, P=0.031) was the strongest determinant CIMT. CONCLUSION: Three year treatment with atorvastatin does not lead to a reduction of CIMT and secondary outcome measures, despite a decrease in total cholesterol and LDL levels. Hypertensive CoA demonstrate the highest CIMT and the largest CIMT progression. Blood pressure control should be the main focus in CoA to decrease cardiovascular risk.

Bicuspid stenotic aortic valves: clinical characteristics and morphological assessment using MRI and echocardiography.

BACKGROUND: Bicuspid aortic valve (BAV) is one of the most common congenital heart defects with a population prevalence of 0.5% to 1.3%. Identifying patients with BAV is clinically relevant because BAV is associated with aortic stenosis, endocarditis and ascending aorta pathology. METHODS AND RESULTS: Patients with severe aortic stenosis necessitating aortic valve replacement surgery were included in this study. All dissected aortic valves were stored in the biobank of the University Medical Centre Utrecht. Additionally to the morphological assessment of the aortic valve by the surgeon and pathologist, echocardiographic and magnetic resonance imaging (MRI) images were evaluated. A total of 80 patients were included of whom 32 (40%) were diagnosed with BAV by the surgeon (gold standard). Patients with BAV were significantly younger (55 vs 71 years) and were more frequently male. Notably, a significant difference was found between the surgeon and pathologist in determining valve morphology. MRI was performed in 33% of patients. MRI could assess valve morphology in 96% vs 73% with echocardiography. The sensitivity of MRI for BAV in a population of patients with severe aortic stenosis was higher than echocardiography (75% vs 55%), whereas specificity was better with the latter (91% vs 79%). Typically, the ascending aorta was larger in patients with BAV. CONCLUSION: Among unselected patients with severe aortic valve stenosis, a high percentage of patients with BAV were found. Imaging and assessment of the aortic valve morphology when stenotic is challenging.

Effects of high-dose insulin infusion on left ventricular function in normal subjects.

Background. Only a few studies have reported on the effect of high-dose insulin (HDI) infusion on cardiac function in healthy volunteers. Methods. We studied ten healthy volunteers with low-dose dobutamine (LDD, 10 mug/kg/min) echo-cardio-graphy and HDI echocardiography (insulin administration for one hour) by volume and Doppler analysis. Results. During LDD, cardiac output increased from 5.7+/-1.3 l/min to 9.0+/-2.1 l/min (p<0.001) and during HDI from 5.5+/-1.2 l/min to 6.2+/-1.1 l/min (p=0.048). Increase was not only due to increase in frequency, which was only present in the LDD study, but also due to increase in stroke volume (from 82+/-15 ml to 110+/-23 ml, p<0.001 during LDD and from 82+/-16 ml to 93+/-24 ml, p=0.014 during HDI). The increase in stroke volume was the result of a decrease in end-systolic volume with an unchanged end-diastolic volume. Conclusion. High-dose insulin infusion results in increased cardiac output by improving systolic myocardial function. (Neth Heart J 2010;18:183-9.).

Contrast-enhanced versus non-enhanced three-dimensional echocardiography of left ventricular volumes.

BACKGROUND: In three-dimensional echocardiography (3DE), individual endocardial trabeculae are not clearly visible necessitating left ventricular (LV) volumes to be measured by tracing the innermost endocardial contour. Ultrasound contrast agents aim to improve endocardial definition, but may delineate the outermost endocardial contour by filling up intertrabecular space. Although measurement reproducibility may benefit, there may be a significant influence on absolute LV volume measurements. METHODS: Twenty patients with a recent myocardial infarction and good ultrasound image quality underwent 3DE using the TomTec Freehand method before and during continuous intravenous contrast infusion. LV volumes were measured offline using TomTec Echo-Scan software. RESULTS: The use of contrast enhancement increased end-diastolic (110+/-35 vs. 144+/-53 ml; p<0.01) and end-systolic volume measurements (68+/-31 vs. 87+/-45 ml; p<0.01) significantly compared with non-contrast; the ejection fraction remained unchanged (40+/-13 vs. 41+/-14%, p=NS). Measurement reproducibility did not improve significantly, however. CONCLUSION: Volumes measured by 3DE are significantly larger when ultrasound contrast is used. Possibly, intertrabecular space comprises a substantial part of the LV cavity. In the presence of an adequate apical acoustic window, ultrasound contrast does not improve LV volume measurement reproducibility. (Neth Heart J 2008;16:47-52.).

Predictive value of markers of myocardial reperfusion in acute myocardial infarction for follow-up left ventricular function.

This study evaluated recently suggested invasive and noninvasive parameters of myocardial reperfusion after acute myocardial infarction (AMI), assessing their predictive value for left ventricular function 4 weeks after AMI and reperfusion defined by myocardial contrast echocardiography (MCE). In 38 patients, angiographic myocardial blush grade, corrected Thrombolysis In Myocardial Infarction frame count, ST-segment elevation index, and coronary flow reserve (n = 25) were determined immediately after primary percutaneous transluminal coronary angioplasty (PTCA) for first AMI, and intravenous MCE was determined before, and at 1 and 24 hours after PTCA to evaluate myocardial reperfusion. Results were related to global wall motion index (GWMI) at 4 weeks. MCE 1 hour after PTCA showed good correlation with GWMI at 4 weeks (r = 0.684, p <0.001) and was in an analysis of variance the best parameter to predict GWMI 4 weeks after AMI. The ST-segment elevation index was close in its predictive value. Considering only invasive parameters of reperfusion myocardial blush grade was the best predictor of GWMI at 4 weeks (R(2) = 0.3107, p <0.001). A MCE perfusion defect size at 24 hours of > or =50% of the MCE perfusion defect size before PTCA was used to define myocardial nonreperfusion. In a multivariate analysis, low myocardial blush grade class was the best predictor of nonreperfusion defined by MCE. Thus, intravenous MCE allows better prediction of left ventricular function 4 weeks after AMI than other evaluated parameters of myocardial reperfusion. Myocardial blush grade is the best predictor of nonreperfusion defined by MCE and is the invasive parameter with the greatest predictive value for left ventricular function after AMI. Coronary flow parameters are less predictive.

Intermittent harmonic imaging and videodensitometry significantly enhance ability of intravenous air-filled ultrasonographic contrast agent to produce ventricular and myocardial opacification.

We used visual and videodensitometric evaluation to investigate the influence of intermittent harmonic imaging (IHI) compared with intermittent fundamental imaging on cavity and myocardial signal intensity after administration of the air-filled transpulmonary contrast agent BY963. Twelve patients were studied with intermittent fundamental imaging and IHI after administration of 5 mL and 10 mL of contrast agent. Contrast effect was graded in the parasternal short-axis view. Visually, IHI improved opacification of both the right and left ventricular cavities, especially the left. Densitometrically, right ventricular opacification did not differ significantly between imaging modalities, whereas left ventricular cavity opacification was significantly higher when using IHI. Myocardial opacification was observed in a small minority of segments when assessed by visual estimation, whereas videodensitometry revealed opacification in 42 of 48 anterior, 39 of 48 posterior, and 42 of 48 septal segments. Differences were not significant between doses. We conclude that with IHI and densitometry, air-filled contrast agents like BY963 show significantly improved performance in producing cavity and myocardial contrast effects.

Myocardial contrast echocardiography: clinical benefit and practical issues.

Real-time bedside evaluation of myocardial perfusion after intravenous application of microbubbles is the ultimate goal for contrast echocardiography. Over the past decade rapid evolution has occurred in the development of contrast agents, ultrasound equipment tailored to their detection, and image interpretation. This article offers a review of the basic concepts of the technique's background, contrast agent design, and imaging technology. The major clinical indications of myocardial contrast echocardiography are evaluation of acute ischemic syndromes, diagnosis of viable myocardium following AMI, and the detection of CAD using stress contrast perfusion imaging. Furthermore, the article addresses the most significant practical problems and suggested solutions to master those problems. As major new achievements are realistic expectations for the first decade of the twenty-first century, we conclude that the coupling of a new generation of contrast agents with innovative echocardiographic instrumentation will ultimately enable the full potential of myocardial contrast echocardiography to be realized which may revolutionize modern echocardiography.

Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angioplasty [correction of angiography] in patients with acute myocardial infarction.

BACKGROUND: This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery. METHODS AND RESULTS: Twenty-five patients with first AMI underwent intravenous MCE with NC100100 with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the "no-reflow" region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR >/=1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. MCE ratio to the risk region was smaller in the recovery group compared with the nonrecovery group (34+/-49% vs 81+/-46%, P=0.009). A ratio to the risk region of

Affinity chromatography with the immobilized agonist N-0434 yields an active and highly purified preparation of the dopamine D-2 receptor from bovine striatum.

Partial purification of the dopamine D-2 receptor from bovine striatum, solubilized in the presence of 1% digitonin, was obtained by chromatography on wheat germ lectin agarose. The preparation was purified approximately 10-fold. The stability of the receptor preparation was considerably improved and non-specific protein absorption on the affinity gel used later was decreased. Further purification was achieved on a column containing a D-2-selective agonist, N-0434. Approximately 90% of the receptor activity was bound to the gel and 20-40% of the activity could be eluted by pH shock. The total purification factor after one affinity chromatography step was estimated to be at least 1500. An active preparation of at least 20% purity was obtained after a second cycle of affinity chromatography. This corresponds to an enrichment of more than 5000 times compared to the solubilized receptor preparation.