Ann Belmans

Temporal Trends in Survival to Adulthood Among Patients Born With Congenital Heart Disease From 1970 to 1992 in Belgium

Background— Over the past decades, the life expectancy of individuals with congenital heart disease (CHD) has increased significantly. However, precise estimates for survival to adulthood are scarce for patients with CHD. We investigated the proportion of CHD patients born between 1990 and 1992 who survived into adulthood. We also compared their survival with that of CHD patients born in earlier eras and evaluated survival as a function of the type of heart defect. Methods and Results— We reviewed the CHD program administrative and clinical database at the University Hospitals Leuven (Leuven, Belgium) and analyzed the records of 7497 CHD patients born from 1970 to 1992. Survival to 18 years of age in patients born between 1990 and 1992 was 88.6% (95% confidence interval [CI], 86.3% to 90.5%), which was significantly greater than that of patients born in previous decades (P<0.0001). For patients born between 1990 and 1992, survival into adulthood for those with mild heart defects was 98.0% (95% CI, 95.8% to 99.1%), whereas survival for those with moderate- and severe-complexity heart defects was 90.0% (95% CI, 86.8% to 92.5%) and 56.4% (95% CI, 47.4% to 64.5%), respectively. Analysis per heart defect confirmed these findings, demonstrating that patients with univentricular heart (49.1% [95% CI, 30.8% to 65.1%]) and hypoplastic left heart syndrome (7.5% [95% CI, 0.6% to 26.6%]) had the poorest survival rate. Conclusion— This study demonstrates that almost 90% of children with CHD have the prospect of surviving into adulthood.

Thrombolysis during resuscitation for out-of-hospital cardiac arrest.

BACKGROUND Approximately 70% of persons who have an out-of-hospital cardiac arrest have underlying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival. METHODS In a double-blind, multicenter trial, we randomly assigned adult patients with witnessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardiopulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. RESULTS After blinded review of data from the first 443 patients, the data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenecteplase was administered to 525 patients and placebo to 525 patients; the two treatment groups had similar clinical profiles. We did not detect any significant differences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neurologic outcome (P=0.69). There were more intracranial hemorrhages in the tenecteplase group. CONCLUSIONS When tenecteplase was used without adjunctive antithrombotic therapy during advanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)

High dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction

AIMS Previous studies have suggested that intravenous administration of adenosine improves myocardial reperfusion and reduces infarct size in ST-elevation myocardial infarction (STEMI) patients. Intracoronary administration of adenosine has shown conflicting results. METHODS AND RESULTS In a prospective, single-centre, double-blind, placebo-controlled clinical study, we assessed whether selective intracoronary administration of adenosine distal to the occlusion site immediately before initial balloon inflation results in myocardial salvage and decreased microvascular obstruction (MVO) as assessed with cardiac magnetic resonance imaging (MRI). Using a combination of T(2)-weighted and contrast-enhanced sequences, myocardial salvage index (MSI) was defined as the percentage of the area at risk that did not become necrotic. We randomized 112 patients presenting with STEMI within 12 h from symptom onset to selective intracoronary administration of adenosine 4 mg or matching placebo. In 100/110 (91%) patients receiving study drug, MRI was performed on Days 2-3. No significant difference in MSI was found between adenosine- and placebo-treated patients: 41.3% (20.8, 66.7) vs. 47.8% (39.8, 60.9) [median (Q1, Q3)] (P = 0.52). The extent of MVO was comparable in both groups, with a trend favouring the placebo group: 2.4 g (0.0, 6.8) vs. 5.9 g (0.0, 12.8) after adenosine (P = 0.07). TIMI flow grade, TIMI frame count, myocardial blush grade, and ST-segment resolution after primary percutaneous coronary intervention were similar between groups. After 4 months, infarct size was similar in both treatment groups. CONCLUSION We found no evidence that selective high-dose intracoronary administration of adenosine distal to the occlusion site of the culprit lesion in STEMI patients results in incremental myocardial salvage or a decrease in microvascular obstruction.

Differential Effects of Progenitor Cell Populations on Left Ventricular Remodeling and Myocardial Neovascularization After Myocardial Infarction

OBJECTIVES We compared biological repair after acute myocardial infarction (AMI) with selected porcine progenitor cell populations. BACKGROUND Cell types and mechanisms responsible for myocardial repair after AMI remain uncertain. METHODS In a blinded, randomized study, we infused autologous late-outgrowth endothelial progenitor cells (EPC) (n = 10, 34 +/- 22 x 10(6) CD29-31-positive, capable of tube formation), allogeneic green fluorescent peptide-labeled mesenchymal stem cells (MSC) (n = 11, 10 +/- 2 x 10(6) CD29-44-90-positive, capable of adipogenic and osteogenic differentiation), or vehicle (CON) (n = 12) in the circumflex artery 1 week after AMI. Systolic function (ejection fraction), left ventricular (LV) end-diastolic and end-systolic volumes, and infarct size were assessed with magnetic resonance imaging at 1 week and 7 weeks. Cell engraftment and vascular density were evaluated on postmortem sections. RESULTS Recovery of LV ejection fraction from 1 to 7 weeks was similar between groups, but LV remodeling markedly differed with a greater increase of LV end-systolic volume in MSC and CON (+11 +/- 12 ml/m(2) and +7 +/- 8 ml/m(2) vs. -3 +/- 11 ml/m(2) in EPC, respectively, p = 0.04), and a similar trend was noted for LV end-diastolic volume (p = 0.09). After EPC, infarct size decreased more in segments with >50% infarct transmurality (p = 0.02 vs. MSC and CON) and was associated with a greater vascular density (p = 0.01). Late outgrowth EPCs secrete higher levels of the pro-angiogenic placental growth factor (733 [277 to 1,214] pg/10(6) vs. 59 [34 to 88] pg/10(6) cells in MSC, p = 0.03) and incorporate in neovessels in vivo. CONCLUSIONS Infusion of late-outgrowth EPCs after AMI improves myocardial infarction remodeling via enhanced neovascularization but does not mediate cardiomyogenesis. Endothelial progenitor cell transfer might hold promise for heart failure prevention via pro-angiogenic or paracrine matrix-modulating effects.

Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy.

Objective Achalasia is a chronic motility disorder of the oesophagus for which laparoscopic Heller myotomy (LHM) and endoscopic pneumodilation (PD) are the most commonly used treatments. However, prospective data comparing their long-term efficacy is lacking. Design 201 newly diagnosed patients with achalasia were randomly assigned to PD (n=96) or LHM (n=105). Before randomisation, symptoms were assessed using the Eckardt score, functional test were performed and quality of life was assessed. The primary outcome was therapeutic success (presence of Eckardt score ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for re-treatment, lower oesophageal sphincter pressure, oesophageal emptying and the rate of complications. Results In the full analysis set, there was no significant difference in success rate between the two treatments with 84% and 82% success after 5 years for LHM and PD, respectively (p=0.92, log-rank test). Similar results were obtained in the per-protocol analysis (5-year success rates: 82% for LHM vs 91% for PD, p=0.08, log-rank test). After 5 years, no differences in secondary outcome parameter were observed. Redilation was performed in 24 (25%) of PD patients. Five oesophageal perforations occurred during PD (5%) while 12 mucosal tears (11%) occurred during LHM. Conclusions After at least 5 years of follow-up, PD and LHM have a comparable success rate with no differences in oesophageal function and emptying. However, 25% of PD patients require redilation during follow-up. Based on these data, we conclude that either treatment can be proposed as initial treatment for achalasia. Trial registration numbers Netherlands trial register (NTR37) and Current Controlled Trials registry (ISRCTN56304564).

One-year follow-up of the ASSENT-2 trial: A double-blind, randomized comparison of single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction

BACKGROUND Single-bolus tenecteplase and accelerated alteplase were shown to be equivalent for 30-day mortality rates in the double-blind Assessment of the Safety of a New Thrombolytic (ASSENT-2) study. The aim of this study is to assess mortality rates after 1-year follow-up. METHODS AND RESULTS One-year vital status was obtained from 92.8% of the patients initially enrolled in the ASSENT-2 trial. Completeness of follow-up was similar for both groups. At 1 year, mortality rates were 9.1% for alteplase and 9.2% for tenecteplase (risk ratio, 1.01; 95% CI, 0.91-1.12). The mortality rate between 30 and 365 days after enrollment was 2.6% for alteplase and 2.8% for tenecteplase (risk, 1.07; 95% CI, 0.88-1.30). A lower 30-day mortality rate in patients treated with tenecteplase after 4 hours of symptom-onset persisted at 1-year follow-up (10.9% vs 12.6% for alteplase), but was no longer statistically significant. There were also no significant differences in mortality rates between the 2 treatments in other major subgroups. In a Cox regression model, no significant interaction was observed between treatment assignment and age, sex, time-to-treatment, Killip class, body weight, and history of previous myocardial infarction, infarction location, systolic blood pressure, or heart rate. CONCLUSIONS One year after randomization, mortality rates remain similar in patients with acute myocardial infarction treated with an accelerated infusion of alteplase or a single bolus of tenecteplase.

Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC)

BACKGROUND To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. PATIENTS AND METHODS Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points). RESULTS Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). CONCLUSION Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial

AIMS Little is known about the respective healing responses and clinical efficacy and safety of drug-eluting balloons (DEB) and the second generation of drug-eluting stents (DES) when used to treat in-stent restenosis (ISR). In this study, we set out to compare prospectively the healing characteristics, as assessed by optical coherence tomography (OCT), of DEB versus DES after treatment of ISR in bare metal stents (BMS). METHODS AND RESULTS Fifty patients with BMS ISR were randomised to treatment with a paclitaxel-eluting balloon vs. an everolimus-eluting stent (EES). The primary endpoint was the percentage of uncovered struts, assessed with OCT at nine months, as a marker of vessel wall healing. A mean of 366±135 and 636±184 struts were analysed per patient in the DEB and EES groups, respectively. The percentage of uncovered struts per patient was significantly lower with DEB vs. EES (1.4% vs. 3.1%, p=0.025). Mean neointimal hyperplasia area was 2.4±1.08 mm in DEB vs. 1.92±0.67 mm in EES (p=0.1806), while the percentage of malapposed struts per patient was very low in both groups (0.2% vs. 0.3%, p=0.699). At nine months, angiographic in-stent MLD (minimum lumen diameter) was lower (2.13 vs. 2.54 mm, p=0.006), while diameter stenosis (26.4 vs. 11.4%, p=0.002), and LLL (0.28 vs. 0.07 mm, p=0.1) were higher after DEB compared to EES. During one-year follow-up, we did not observe differences in the rates of death, TLR (target lesion revascularisation) or stent thrombosis. CONCLUSIONS DEB appears to be associated with better healing characteristics, as assessed by stent strut coverage with OCT, but tended to be slightly less effective compared to EES. These findings give support to the use of either DEB or EES as valuable treatment options for ISR. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Unique identifier: NCT 01065532.

Influence of 23 coronary artery disease variants on recurrent myocardial infarction or cardiac death: the GRACE Genetics Study

AIMS A pooled analysis of 14 genome-wide association studies revealed 23 susceptibility loci for coronary artery disease (CAD), thereby providing the most comprehensive genetic blueprint of CAD susceptibility. Here, we evaluated whether these 23 loci also predispose to recurrent myocardial infarction (MI) or cardiac death following an acute coronary syndrome (ACS). METHODS AND RESULTS A total of 2099 ACS patients enrolled in the Global Registry of Acute Coronary Events (GRACE) UK-Belgian study were prospectively followed for a median of 5 years (1668 days). C-allele carriers of the rs579459 variant, which is located upstream of the ABO gene and correlates with blood group A, were independently associated with recurrent MI [multivariable-adjusted hazard ratio (HR) 2.25, CI = 1.37-3.71; P = 0.001] and with recurrent MI or cardiac death [multivariable-adjusted (HR) 1.80, CI = 1.09-2.95; P = 0.021] within 5 years after an index ACS. The association of rs579459 was replicated in 1250 Polish patients with 6 months follow-up after an index ACS [multivariable-adjusted (HR) 2.70, CI = 1.26-5.82; P = 0.011 for recurrent MI]. Addition of rs579459 to a prediction model of 17 clinical risk factors improved risk classification for recurrent MI or cardiac death at 6 months as calculated by the integrated discrimination improvement method (P = 0.037), but not by C-statistics (P = 0.096). CONCLUSION In this observational study, rs579459 was independently associated with adverse cardiac outcome after ACS. A weak improvement in clinical risk prediction was also observed, suggesting that rs579459 should be further tested as a potentially relevant contributor to risk prediction models for adverse outcome following ACS.

Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis A Report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort)

Background: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. Methods: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. Results: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm2. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1–99.9), 96.6% (92.4–98.5), 34.3% (15.0–60.7), and 9.6% (6.2–14.5) and malapposed struts was 21.8% (8.4–45.6), 8.5% (4.6–15.3), 6.7% (2.5–16.3), and 2.0% (1.2–3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. Conclusions: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST.