ECG Examination Research Articles

Behavioral disorders in rats with chronic myocardial dysfunction.

Observation of cardiologists and psychiatrists suggest that cardiovascular diseases and depression are the most common and frequent comorbid conditions. Therefore the aim of the study was to identify behavioral disorders in rats on the background of myocardial dysfunction in the experiment. Material of the research: 60 adult male rats of Wistar line, weighing 200-220 g, divided into 2 groups - control and experimental. Myocardial dysfunction was modeled by intraperitoneal injection of doxorubicin by 5 mg/kg of animal weight. To verify the model of myocardial dysfunction ECG and histological examination of the myocardium were performed. Evaluation of higher divisions of the CNS reactions was performed using the open field method by such indicators: vertical and horizontal motor activity (decreased by 71,4%), acts and defecation boluses (down by 85-88%), the number of burrows (decreased by 57-90%), grooming (decreased by 23%), all parameters were reliable (in p<0,05). There was a gradual decline of rats’ emotionality, CNS depression and increased anxiety. It was found that behavioral disorders in the experiment were typical for anxiety and depression states.

Image Case: Aortic Dissection: Uncommon Cause of Agonizing Abdominal Pain

We reported a 59 years old male presented with severe agonizing abdominal pain just to the left side of the umbilicus and referred to the left shoulder. The patient was hypertensive on bisoprolol but no history of acute coronary syndrome. He was misdiagnosed at a primary health care 5 days before diagnosis. When presented he was hemodynamically stable with blood pressure 130/80. On abdominal examination mildly tender oblong mass was felt to the side of the umbilicus. The ECG examination was irrelevant. On gray scale abdominal ultrasonographgy a double channel abdominal aorta was seen that was later confirmed by Doppler study. CT angiography showed large intimal dissection sparing the aortic arch distal to the left subclavian artery and extends all through the descending thoracic and abdominal aorta till the bifurcation with small extension to the left common iliac artery.

Acute Cholecystitis Mimics Ischemic Cardiac Disease: A Case Report and Review of the Literature

Chest pain and shortness of breath are typical indicators of cardiac problem and may lead to life threatening conditions. Nevertheless, these symptoms may also be associated with a non-cardiac condition clinically such as cholecystitis. We have reported 4 cases in a period of 6 months wherein the patients presented with cardiac-like symptom show ever; they were subsequently diagnosed with non-cardiac problems. Two patients presented with severe chest pain and shortness of breath mimicking angina pectoris. They were admitted to the intensive care unit for emergency management. The ECG findings were normal. There were two other patients who also presented with severe chest pain and shortness of breath with ST segment elevation during the ECG examination. The abdominal ultrasound in all the 4 patients showed typical features of acute calculus cholecystitis. All patients were young (30 - 36 years of age) females who were obese (BMI ranging from 30 - 34). Cholecystectomy was performed which led to improved symptoms postoperatively and ECG changes became normal.

Cardiovascular risk assessment for the use of ADHD drugs in children

Drug therapy for ADHD (Attention Deficit Hyperactivity Disorder) has generally been regarded as safe. ECG screening of healthy children and adolescents before initiating this type of treatment appears to be usual in Norway, despite recommendations that ECGs should only be undertaken in individuals who are at risk. The purpose of this article is to clarify relevant guidelines for cardiovascular risk assessment for the use of ADHD drugs in children and adolescents, as well as to propose practical recommendations. The article is based on a literature search in PubMed completed on 1 October 2013, and on the author's own clinical experience and discretionary assessments. The use of CNS stimulants and atomoxetine is associated with a slight rise in blood pressure and pulse rate, as well as small changes in QT interval. A small percentage of patients (5-10%) experience a clinically significant rise in blood pressure and pulse rate. Sudden death does not appear to occur more frequently in children and adolescents taking ADHD drugs in therapeutic doses than in children and adolescents who do not use such drugs. There is little knowledge available on the long-term effects of ADHD drugs on the cardiovascular system of otherwise healthy individuals, or on the risk related to the use of ADHD drugs in children and adolescents with cardiac disease. The drugs are thought to increase the risk of sudden cardiac death in some arrhythmia syndromes. Our assessment is that caution should be exercised in the use of ADHD drugs in children with potentially dangerous cardiac arrhythmias. We recommend clinical examination and a thorough medical history review in order to identify individuals at risk before initiating drug therapy, and also suggest that it is not necessary for healthy children to be given an ECG examination before introducing ADHD drugs. In children with known cardiac disease, arrhythmia or risk factors for cardiac disease, ADHD treatment should be undertaken in consultation with a medical specialist with competence in pediatric cardiology.

Does type of cardioplegia affect myocardial and cerebral outcome in pediatric open cardiac surgeries?

Background A single-dose strategy for cardioplegia is desired in pediatric congenital cardiac surgery, especially in repair of complex congenital defects. The hypothesis of this study is that a single infusion of Bretschneider HTK solution may offer myocardial and cerebral protection superior to repeated doses of a cold oxygenated blood cardioplegic solution in pediatric congenital cardiac surgery. Patients and methods Sixty patients who underwent congenital cardiac repair using cardiopulmonary bypass were grouped randomly to receive either a single dose of Custodiol (group A) or repeated oxygenated blood cardioplegia (group B). Echocardiography, ECG, and microscopic examination were used to evaluate left-ventricular function and structure. Myocardial injury was assessed with creatine kinase MB and serum troponin T, whereas cerebral outcome was assessed by jugular venous oxygen saturation. Patients were also neurologically examined and studied by brain computed tomography for gross neurological manifestation of cerebral ischemia or infarction preoperative and 2 days postoperatively. Results Myocardial enzymes and oxygen extraction were significantly high in group B compared with group A. Ultrastructure evaluation and cerebral outcome were significantly better in group A than in group B. Conclusion A single dose of an HTK cardioplegic solution provides better myocardial and cerebral protection than repeated doses of oxygenated blood cardioplegia during pediatric congenital cardiac surgery.

The observation of adverse reactions of Ziprasidone in the treatment of 32 cases of female schizophrenia

Objective To discuss the safety of Ziprasidone in female schizophrenia patients.Methods 32 cases of female schizophrenia were treated with Ziprasidone for 6 weeks.Laboratory examination and ECG examination were carried out before and 2,4,6 weeks after treatment.Investigated the influence of Ziprasidone on lipid,blood glucose,body weight and ECG in female schizophrenia patients.Results The levels of triglyceride,cholesterol and body weight of female schizophrenia patients after treatment significantly rose than those before treatment,with statistical significant differences (P ＜ 0.05); QT and QTC interval 4 weeks after treatment significantly prolonged,with statistical significant differences (P ＜ 0.05).Conclusion Ziprasidone has influence on serum lipid,body weight and QT interval in female schizophrenic patients,but not on blood glucose. Key words: Ziprasidone; Schizophrenia; Blood glucose; ECG; Serum lipid; Body weight

Home Telemonitoring reduces hospitalization for Heart Failure in an NHS service: a Propensity-Matched Analysis

Purpose: Several reports suggest that Home Telemonitoring (HTM) may reduce mortality and possibly hospitalizations for heart failure (HF) but others have not confirmed this. Whether HTM is more or less effective in clinical practice than in clinical trials is uncertain. This analysis investigated variations in outcome of patients with Chronic Heart Failure (CHF) receiving HTM in a clinical service compared to those receiving conventional care. Purpose: Several reports suggest that Home Telemonitoring (HTM) may reduce mortality and possibly hospitalizations for heart failure (HF) but others have not confirmed this. Whether HTM is more or less effective in clinical practice than in clinical trials is uncertain. This analysis investigated variations in outcome of patients with Chronic Heart Failure (CHF) receiving HTM in a clinical service compared to those receiving conventional care. Methods: As part of the local heart failure service provision for the City of Kingston-upon-Hull (population circa 288,000), 225 patients were enrolled in the HTM service between April 2008 and May 2012 during which time 1822 patients had been registered in an out-patient service. A literature review was carried out, and this together with recommendations from clinicians and completeness of data resulted in 54 features that were chosen as candidate covariates for the calculation of propensity scores (PS). Key co-variates included age, sex, weight, NT-proBNP, Blood pressure, Creatinine, Urea, Heart rate, Diabetic, Hypertension, Beta blocker, etc. Outcomes of interest were (time to first International Congress on Telehealth and Telecare 2013, London, July 01-03, 2013. 2 International Journal of Integrated Care –Volume 13, 20 November –URN:NBN:NL:UI:10-1-115718– http://www.ijic.org/ event) all-cause hospitalization or death, cardiovascular (CV) hospitalization or death, all-cause mortality and CV mortality. Results: Before PS matching, there were 645 patients in the control group and 106 patients in the HTM group, who had an ECG, Echo, blood test, medication and physical examination during a specified time window. PS was calculated using a non-parsimonious multivariable logistic regression model and 80 pairs of patients with a similar PS (to two decimal places) were matched. Risks of the four types of outcomes were then analysed using Kaplan-Meier methods and are plotted. At two year, all-cause hospitalization or death was 37.3% in the HTM group and 59.5% in the control group (p = 0.008); CV hospitalization or death was 34.2% in the HTM group and 51.8% in the control group (p = 0.046); all-cause mortality was 23.4% in the HTM group and 21.2% in the control group (p = 0.531); CV mortality was 16.2% in the HTM group and in 13.9% in the control group (p = 0.629). Conclusions: In this analysis, HTM was associated with a lower incidence of (all-cause or CV) hospitalisation or death but not all-cause or CV mortality.

An infant with hypercalcemia: Questions

A 6-month-old male infant born by normal vaginal delivery (birth weight 3.150 kg, length 49 cm) and affected by hypospadias underwent renal ultrasound scan (Fig. 1). Expert advice was required after an “uncertain renal US report”. The patient suffered decreased appetite, vomiting, constipation, polyuria and polydipsia during the previous 2 months. At our appointment, we found hypotonia, irritability, failure to thrive, anterior fontanelle 1.5×1 cm, and moderate dehydration. His mother reported that the infant was taking no drugs except prophylaxis with vitamin D (400 IU/day). Serum chemistry was as follows: calcium 18.67 mg/dl (normal range, 8.4–10.2 mg/dl), urea 65 mg/dl (10–50 mg/ dl), creatinine 0.45 mg/dl, phosphorus 5.7 mg/dl, Ca×P 106 mg (normal value <55 mg), venous pH 7.38. Na, K, Cl, Mg, HCO3, ABE, glycemia, AST, ALT, γGT, bilirubin, alkaline phosphatase and complete blood count were within normal limits. Urinary electrolyte concentrations: calcium/ creatinine ratio 1.27 mg/mg, uric acid/creatinine 0.45 mg/dl of glomerulor filtration rate, beta2 microglobulin 0.4 mg/l (nv: <0.3 mg/l). ECG, cardiologic and oculistic examination, and blood pressure monitoring were normal. We started hyperhydration (NaCl 0.9 % 7 ml/kg/h) to reduce calcemia. After 12 h, the blood calcium was 15.2 mg/ dl. Therefore we added furosemide (1 mg/kg intravenously twice a day) and methylprednisolone (1 mg/kg once a day). After 4 days of therapy, the blood calcium was 13.8 mg/dl and urinary calcium/creatinine ratio was 2.61 mg/mg. The clinical conditions of the patient improved after 4 days (no vomiting, increased appetite). The serum level of calcium did not decrease after 6 days of therapy with furosemide and methylprednisolone, remaining at 13.8 mg/dl.

The effect of precordial lead displacement on ECG morphology

Inaccurate electrode placement and differences in inter-individual human anatomies can lead to misinterpretation of ECG examination. The aim of the study was to investigate the effect of precordial electrodes displacement on morphology of the ECG signal in a group of 60 patients with diagnosed cardiac disease. Shapes of ECG signals recorded from precordial leads were compared with signals interpolated at the points located at a distance up to 5 cm from lead location. Shape differences of the QRS and ST-T-U complexes were quantified using the distribution function method, correlation coefficient, root-mean-square error (RMSE), and normalized RMSE. The relative variability (RV) index was calculated to quantify inter-individual variability. ECG morphology changes were prominent in all shape parameters beyond 2 cm distance to precordial leads. Lead V2 was the most sensitive to displacement errors, followed by leads V3, V1, and V4, for which the direction of electrodes displacement plays a key role. No visible changes in ECG morphology were observed in leads V5 and V6, only scaling effect of signal amplitude. The RV ranged from 0.639 to 0.989. Distortions in ECG tracings increase with the distance from precordial lead, which are specific to chosen electrode, direction of displacement, and for ECG segment selected for calculations.

Age and Sex Effects on the Single- and Multiple-Dose Safety and Pharmacokinetics of the New Renin Inhibitor ACT-178882

To investigate the effect of age and sex on the single- and multiple-dose safety and pharmacokinetics of ACT-178882, a new direct renin inhibitor. In the single-dose, open-label part of the study, healthy young and elderly male and female subjects received a dose of 300 mg ACT-178882. In the multiple-dose, double-blind, placebo-controlled part of the study, healthy elderly male and female subjects received ACT-178882 (300 or 600 mg) or placebo once-a-day for 14 days. Mild headache and diarrhea were the most common adverse events in the single- and multiple-dose parts, respectively. The frequency of diarrhea increased dose dependently, and no placebo subjects reported this adverse event. Administration of ACT-178882 did not result in any clinically relevant changes in ECG, vial signs, clinical laboratory, body weight, or physical examination. In the single-dose part and independent of sex, values for Cmax and AUC0-∞ were about 85% higher in elderly compared with young subjects, and t1/2 was about 5 h longer (29.3 vs. 24.1 h). In both age groups, plasma ACT-178882 concentrations were slightly higher in female versus male subjects. Following multiple-dose administration to elderly subjects, accumulation of ACT-178882 was moderate, about 1.8-fold, t1/2 was unchanged as compared with single-dose administration, sex effects were minimal, and the increase in the exposure with increasing dose appeared less than dose proportional. Overall, single- and multiple-dose administration of ACT-178882 was well tolerated. No dose adaptation based on sex is necessary, whereas a dose reduction based on age could be considered.

GW24-e2156 Transcatheter closure of patent ductus arteriosus in children with body weight less than or equal 8Kg

ObjectivesTo explore the interventional experience of transcatheter closure of patent ductus arteriosus (PDA) in children with body weight ≤ 8Kg.MethodsFrom May 2001 to October 2012, 81 children with body weight...

SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients

An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients. We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring. The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210 ± 25 vs. 195 ± 25 ms; P=0.036; and QRS, 112 ± 10 vs. 105 ± 9 ms; P=0.030). These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes.

Cardiac anomalies in individuals with the 18q deletion syndrome; report of a child with Ebstein anomaly and review of the literature

Individuals with the 18q deletion syndrome are presented with various clinical characteristics, including cardiac anomalies in 24–36% of the reported cases. Nonetheless, genotype–phenotype correlations for cardiac anomalies in the 18q deletion syndrome have rarely been reported. We report on two girls with a terminal 18q deletion, one in whom an Ebstein anomaly and Wolff–Parkinson–White syndrome were detected and the other with multiple valve stenosis and a ventricular septal defect. The genotype and cardiac abnormalities of these girls and 17 other individuals with a de novo 18qter deletion reported in the literature are reviewed. All 19 individuals shared a small overlapping deletion region between 18q22.3q23. The most common cardiac defects detected were pulmonary valve anomalies and atrial septal defects. Ebstein anomaly, a rare cardiac malformation, was diagnosed in two individuals. Additional molecularly based genotype–phenotype studies are needed in order to pinpoint candidate genes within this region that contribute to normal cardiac development. A careful cardiac evaluation consisting of physical examination, ECG and ultrasound examination should be performed in all individuals diagnosed with the 18q deletion syndrome.

Aborting STEMI: What treatment opportunities may Smart-Phone ECGs give us prior to first medical contact to facilitate primary PCI?

The diagnosis of STEMI is based classically on a “cross-sectional” examination of the presenting ECG at first medical contact. This approach may be modified as patients can now record ECG strips on an iPhone [1]. In the near future, multi-electrode recordings with electrodes embedded on a pad or a vest which the patient places or wears over the chest may provide “longitudinal” information to the evolutionary ECG changes of STEMI prior to first medical contact. A recent article forecasted that with Smart Phone ECG monitoring the longitudinal ECG information will allow STEMI to be categorized on a gray-scale ranging from large rapidly progressive STEMI to small stuttering STEMI [1].

PP-279 ABLATION OF THE TYPICAL CAVOTRICUSPID ISTHMUS-DEPENDENT ATRIAL FLUTTER AND ATRIOVENTRICULAR NODAL REENTRY TACHYCARDIA IN A PATIENT WITH OPERATED TETRALOGY OF FALLOT

Introduction: Cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) is the most common arrhythmia in operated Tetralogy of Fallot (ToF) patients. Here, we report the successful ablation of a typical counterclockwise AFL and reverse clockwise AFL in a patient with operated ToF. Case report: A 35-year-old male had previously undergone total corrective surgery for ToF 27 years before admitted to our clinic. He suffered from tachyarrhythmias for 3 months, and his symptoms had worsened in the last 1 month with the manifestation of paroxysmal typical AFL. Baseline ECG revealed first degree AV block and right ventricular hypertrophy signs. Upon examination of the 12-lead ECG recorded during palpitation, we observed no visible P waves and inferior axis and thus considered the possibility of AVNRT. Transthoracic and transesophageal echocardiography revealed an incomplete closure of the tricuspid valve with severe tricuspid regurgitation and a dilated right atrium in the apical 4-chamber view. Electrophysiological investigation revealed both clockwise and anticlockwise AFL (Figures 1a,b).

PP-035 EFFORT DYSPNEA CAUSED BY AN UNUSUAL MEMBRANE LOCALIZED IN THE LEFT VENTRICLE OF THE HEART

PP-035 EFFORT DYSPNEA CAUSED BY AN UNUSUAL MEMBRANE LOCALIZED IN THE LEFT VENTRICLE OF THE HEART R. Kutlu, M.E. Memetoglu, O.Z. Arik, H. Karal, E. Avsar. Department of Cardiology, Gumushane State Hospital, Gumushane, Turkey; Department of Cardiovascular Surgery, Gumushane State Hospital, Gumushane, Turkey; Department of Thoracic Surgery, Gumushane State Hospital, Gumushane, Turkey A 40-year-old man was admitted to our cardiology department because of effort dyspnea during the last 2 months. The physical examination, ECG, and blood examination were unremarkable. A transthoracic echocardiogram demonstrated normal left ventricular size and function, and a highly mobile, fibrous membrane attached the interventricular septum at the left apical region of the heart (Figure 1).

Gone Fishing (for Silent Atrial Fibrillation)

Atrial fibrillation (AF) is associated with a stubbornly elevated mortality (3.5% –4% per year in trials),1–4 at odds with the decline in mortality after a first myocardial infarction.5 Furthermore, the prevalence and incidence of AF are increasing as our societies get older,6 and treatment of other acute and chronic cardiac disorders that predispose to AF will further prolong the lives of patients at risk of AF. Hence, there is a need to improve outcomes in patients with AF.7 Article see p 930 AF can present in a variety of clinical scenarios. Some patients suffer so much that they seek specialist help to be relieved from the arrhythmia. Others present with diffuse symptoms, often including fatigue and shortness of breath, and are found to be in AF on clinical or ECG examination. In yet others, AF is an incidental finding when an irregular heartbeat is detected on physical examination and/or an ECG is recorded for other reasons, such as during preoperative assessment. In these patients, the diagnosis of AF is made in time to institute therapy, such as oral anticoagulation, rate control, rhythm control, and therapy of concomitant cardiovascular diseases.8 It is estimated that one third of patients with AF are asymptomatic. Paroxysmal AF, in particular, frequently occurs without patient awareness. Studies in which systematic ECG monitoring is used have suggested that 50% to 70% of AF episodes occur without patient symptoms.9 Some patients are particularly unfortunate, and the diagnosis of AF is made only after presentation with an AF-related complication. The most devastating complication of AF is an acute ischemic stroke. In others, paroxysmal, self-terminating AF may remain undiagnosed even after the …

Angiotensin-converting enzyme I/D gene polymorphism affects early cardiac response to professional training in young footballers

The renin-angiotensin-aldosterone system plays a role in physiological and pathological responses of the heart to both static and dynamic exercise. Previous studies showed that the level of angiotensin II is determined by the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism. We aimed in this study to determine the effect of ACE I/D gene polymorphism on the extent of functional and structural cardiac changes in response to one year of professional football training in young footballers. We studied 68 young male football players and a comparable control group. Besides medical history and clinical examination, 12 lead ECG and transthoracic 2D echocardiography examination were performed. Genotyping of ACE was analyzed using PCR-based technique. There was no statistically significant difference in distribution of genotypes among athletes compared with control subjects. D allele showed a graded effect on both EF (73.55, 67.5 and 60.2%, p=0.03) and PASP (37.6, 26.1 and 21.39 mmHg, p=0.02) in DD, ID and II subjects, respectively. Early cardiac changes in young footballers can be affected by ACE I/D polymorphism. There is a summative effect of the D allele in increasing EF and PASP in response to professional football training.

Mayer–Rokitansky–Kuster–Hauser Type-B Anomaly with MURCS Association and Gonadal Dysgenesis

The Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome affects 1 out of 4,500 women [1]. It is a malformation of the female genitals due to interrupted embryonic development of the mullerian (paramesonephric) ducts in otherwise chromosomally, phenotypically, and endocrinologically normal female. It is second to Turner’s syndrome as a cause of primary amenorrhea and was described by Mayer (1829), Rokitansky (1838), Kuster (1910), and Hauser and Schreiner (1961) in various literature studies, which was later designated as MRKH syndrome. MRKH syndrome is broadly subdivided into type A (typical) having symmetric uterine remnants and normal fallopian tubes and type B (atypical) with asymmetric uterine buds and abnormally developed fallopian tubes and other organ system anomalies. Gonadal agenesis or dysgenesis is a chromosomal aberration with a separate spectrum of anomalies having an overall incidence of about 1:2,500 live birth females, half of which have a mosaic pattern. These patients have multiple somatic abnormalities like short stature, broad chest, webbed neck, low hair line, sometimes low I.Q., cardiac abnormalities (1/3 cases), and renal abnormalities (35–70 %). They usually have pre-pubertal female genitalia, bilateral streak gonads, but usually normal uterus and vagina (Figs ​(Figs1,1, ​,22). Fig. 1 Photograph showing webbing of neck Fig. 2 Photograph showing the absence of left thumb and rudimentary right thumb Case Report An 18-year-old girl with primary amenorrhea attended the O.P.D. with normal I.Q. (1st year college student) and without such family history. On examination, her height is 154 cm, weight—42 kg, with webbing of neck, telecanthus; and her left thumb was absent and right thumb rudimentary. Systemic examination was normal. Breasts were well developed and axillary and pubic hairs were present. On perineal examination, there was a hymenal fringe and blind vagina. Uterus was absent on per rectal examination. Routine examination of blood, ECG, and chest X-ray reported normal. X-ray cervical spine showed fusion of the cervical vertebrae (Klippel Feil Syndrome). Serum FSH, LH, TSH, and testosterone were normal. USG [02/10/07] showed right-sided crossed fused ectopic kidney with normal corticomedullary differentiation, uterus absent, and normal gonads. Diagnostic laparoscopic [04/10/07] finding was asymmetric mullerian nodule [rt > lt] with rudimentary fallopian tubes, and both ovaries were normal with signs of ovulation. Karyotyping was Turner’s mosaics pattern (46XX/45XO). Diagnosis of MRKH type-B with gonadal dysgenesis was made. Vaginoplasty was done on 12/10/07 after proper counseling as parents wanted to arrange marriage. Post-operative period was uneventful.

ACE-536 Increases Hemoglobin in Healthy Postmenopausal Women: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study

AbstractAbstract 3194 Background:ACE-536 is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc domain. ACE-536 acts as a ligand trap for members of the TGF-β superfamily involved in erythropoiesis. ACE-536 promotes late-stage erythrocyte precursor cell differentiation by inhibiting specific TGF-β family ligands. Studies of ACE-536 in wild type animals across several species demonstrated an erythroid response that was rapid in onset, robust, and sustained. ACE-536 was also shown to significantly improve hematologic parameters and correct ineffective erythropoiesis in mouse models of myelodysplastic syndromes (MDS) and β-thalassemia. This study is the first human clinical trial of ACE-536. Methods:This was a single-center, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK, and PD effects of ACE-536 in healthy, postmenopausal women. Screening and baseline hemoglobin values were to be between 11.0 and 14.5 g/dL. Sequential cohorts of 8 subjects each were randomized to receive either ACE-536 (n=6) or placebo (n=2) administered as SC injections on Day 1 and Day 15. ACE-536 dose levels tested (prior to halting dose escalation per protocol due to positive hemoglobin response) were 0.0625, 0.125 and 0.25 mg/kg. The study included pre-specified individual stopping rules for the Day 15 dose for increases in hemoglobin, changes in blood pressure, or ≥ grade 3 adverse events. From Day 1 through Day 57, subjects were assessed for safety by monitoring adverse events, clinical laboratory tests, ECG, vital signs and physical examination. Longer-term follow up visits occurred on Days 71 and 127. Results:A total of 32 subjects were enrolled. The mean (SD) age was 59.4 (5.8) yr (range: 49–71 yr). All subjects in the first cohort (0.0625 mg/kg or placebo) received both doses of ACE-536; all subjects in the second cohort (0.125 mg/kg or placebo) received only one dose of ACE-536 due to study interruption. This dose level was repeated for the third cohort in which subjects received 2 doses; 1 subject in that cohort did not receive the second dose due to elevated blood pressure. Four subjects in the fourth cohort (0.25 mg/kg or placebo) did not receive the second dose due to hemoglobin increase ≥ 1.0 g/dL and one additional subject did not receive the second dose due to an AE of papular rash.There were no serious adverse events or study discontinuations reported. The majority of AEs were considered mild in severity. No clinically meaningful abnormalities in laboratory measures, vital signs, physical exam, or ECG were observed, and no anti-drug antibodies were detected. The mean serum ACE-536 Cmax and AUC after the first dose increased in a dose-proportional manner, with mean time to Cmax 7.7–11.7 days and mean elimination T½ 15.5–18.5 days.The maximum hemoglobin increase from baseline at any timepoint for subjects in the 0.25 mg/kg cohort ranged from 0.6 to 2.0 g/dL (5 of 6 subjects increased ≥1.1 g/dL), with a mean maximum increase of 1.3 g/dL (p<0.001 vs placebo). Mean hemoglobin levels increased in that dose group by at least 0.6 g/dL from Day 8 through Day 57, compared with a mean decrease in the placebo group of up to 0.6 g/dL through Day 43 (see Figure). Small increases in mean reticulocyte count and EPO levels were seen in groups treated with higher doses of ACE-536 as compared with the placebo group. [Display omitted] Conclusions:The preliminary results from this first-in-human phase 1 study show that ACE-536 is associated with a robust and sustained increase in hemoglobin levels in healthy subjects. Dose levels up to 0.25 mg/kg were generally safe and well-tolerated. The PK results support SC dosing of ACE-536 every 3 weeks. These data warrant further evaluation of ACE-536 in clinical trials in patients with disease-associated ineffective erythropoiesis and anemia, such as MDS and β-thalassemia. Disclosures:Attie:Acceleron Pharma, Inc.: Employment. Boyd:Acceleron Pharma, Inc.: Employment. Wilson:Acceleron Pharma, Inc.: Employment. Sherman:Acceleron Pharma, Inc.: Employment.