The progress and significance of QRS duration by electrocardiography in hypoplastic left heart syndrome

Patients with hypoplastic left heart syndrome (HLHS) are now surviving through to Fontan palliation and beyond, however, with increased morbidity and mortality. Prolonged QRSd has become one of the predictors of morbidity and mortality in certain congenital heart diseases. There is limited data characterizing the QRSd in patients with HLHS. We aimed to describe the changes in QRSd at various times during the lifetime and to evaluate whether QRSd correlates with a higher risk of developing a composite endpoint of heart failure, heart transplant, or death. We conducted a retrospective chart review of patients with HLHS who survived Fontan palliation. QRSd was measured on ECGs at various stages pre- and postsurgical palliations and subsequently at 5 year intervals. Patients with a composite endpoint were compared to those without. A total of 89 patients were included in the final analysis. The QRSd increased significantly with time from 68.7 ± 9.0 ms prior to Norwood to 91.0 ± 14.0 ms immediately following Fontan and 104.7 ± 13.6 ms 15 years after Fontan (p \u3c 0.001). The composite endpoint was observed in 28 patients (31.4%). The time trends of QRSd differ so that the patients having the composite endpoint experienced a greater increase in QRSd over time (p = 0.009). Ever having a QRSd of 120 ms or more predicted the composite endpoint with 93% specificity. The area under the curve of the receiver operator curve analysis was 0.596. A Cox regression analysis demonstrated that QRS duration \u3e 120 ms was independently related to a greater frequency of composite endpoint and this was confirmed by a Kaplan-Meier analysis (p = 0.011). This study unveils a novel relationship between QRSd of 120 ms or more with the composite endpoint. Despite the low sensitivity, this finding on a routine surveillance ECG could help identify HLHS Fontan patients at risk for heart failure, heart transplant, or death

Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study

<div><p>The erythrocyte binding antigen region II (EBA-175 RII) is a <i>Plasmodium falciparum</i> ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth <i>in vitro</i>. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg) of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline). The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited <i>P</i>. <i>falciparum</i> growth <i>in vitro</i>, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended.</p><p>Trial registration</p><p>ClinicalTrials.gov. Identifier: <a href="https://clinicaltrials.gov/ct2/show/NCT01026246" target="_blank">NCT01026246</a></p></div

Observed laboratory adverse events for all dose escalation groups.

<p><b>Panel A</b> is for screening prior to enrolment; <b>Panels B</b> and <b>C</b> are for vaccination 1, Day 0 and Day 14 respectively; <b>Panels D</b> and <b>E</b> are for vaccination 2, Day 0 and Day 14 respectively and <b>Panels F, G</b> and <b>H</b> are for vaccination 3, Day 0, Day 14 and Day 28 respectively. Abbreviations: ALT—Alanine Transaminase; AST—Alanine Aminotransferase; CR–Creatinine; BG–Blood glucose; K–Potassium; Na–Sodium; Hb–Hemoglobin; PLT–Platelets; WBC–White Blood Cells.</p

Demographic and baseline characteristics by dose of study population.

<p>Demographic and baseline characteristics by dose of study population.</p

Trial profile.

<p>^a Vaccination was discontinued in one subject due to blood phobia. ^b One subject was excluded from further vaccinations due to severe anemia. ^c One subject migrated out of the country without prior notification. ^d One subject voluntarily withdrew to relocate to another town. ^e One subject discontinued the study and was lost to follow up for safety evaluation after receiving all three vaccinations. All attempts to find this subject failed. Abbreviation: EBA-175 RII-NG–Erythrocyte binding antigen 175 region II non-glycosylated.</p

Anti-EBA-175 RII-NG IgG antibody levels (ELISA units) and growth inhibition activity against <i>P</i>. <i>falciparum</i> 3D7 parasite.

<p><b>Panel A:</b> Geometric mean IgG antibody levels (ELISA units) to the vaccine antigen EBA-175 RII-NG measured in each treatment group on different days (D0 to D194) post vaccination. <b>Panel B:</b> The left y-axis represents mean percentage <i>P</i>. <i>falciparum</i> 3D7 parasite growth inhibition measured for each treatment group on the different days post vaccination plotted as vertical bars. The right y-axis represents mean EBA175 ELISA units (on log 10 scale) used per growth inhibition assay well for each treatment group on the different days post vaccination plotted as lines. One subject in the placebo group recorded the highest anti-EBA-175 RII-NG IgG levels at baseline which persisted throughout the study. Both the high mean EBA 175 ELISA units/GIA well and mean GIA values observed in the placebo group were largely due to this subject. One ELISA unit is the reciprocal of the dilution required to give an optical density = 1 in the standardized assay. Any data point less than the minimal detectable level was assigned as 5 ELISA units in the growth inhibition assay well in the analysis. Vaccinations occurred on Days 0, 28 and 180. Blood samples were drawn for immunogenicity prior to vaccination. Abbreviations: EBA-175 RII-NG–Erythrocyte binding antigen 175 region II non-glycosylated; IgG–Immunoglobulin G; GIA–Growth inhibition assay.</p

Proportion of subjects with 4-fold increase from baseline in anti-EBA175 antibody response.

<p>Proportion of subjects with 4-fold increase from baseline in anti-EBA175 antibody response.</p

Adverse events by severity vaccine dose and frequency of vaccinations.

<p>Adverse events by severity vaccine dose and frequency of vaccinations.</p