Marc Ovadia

Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants

Background— Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results— We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions— Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Human experience with amiodarone in the embryonic period

Reported use of amiodarone in pregnancy is rare, despite increased use of the drug in women of child-bearing age. Use of amiodarone in late pregnancy has been reported and a lithium-like fetopathy discovered1–5 consisting of hypothyroidism and goiter (due to its lithium-like antithyroid actions). There are only 2 reports of amiodarone use during the embryonic period and organogenesis.6,7 Both gravidae had relatively low drug exposure. No congenital malformation was observed. Studies in rodents suggest the possibility of additional embryonic and fetal toxicities.8,9 We report 3 cases of human amiodarone use during the first trimester at a substantially higher dose than in the previous cases. We detail one major malformation due to abnormal organogenesis, and we report fetal amiodarone and N-desethyl-amiodarone levels for the first time.

Conduction System Disease in Fetuses Evaluated for Irregular Cardiac Rhythm

Objectives: To determine the prevalence of 1st and 2nd degree AV block in fetuses with an irregular cardiac rhythm, and to summarize outcome of these pregnancies. Background: The diagnosis of irregular cardiac rhythm or ‘skipped beats’ includes isolated ectopy that resolves spontaneously. Recently, Doppler measurements of the ‘mechanical’ PR interval have been shown to identify AV conduction disease prenatally. Prenatal therapy of these conduction abnormalities may limit the progression to more advanced disease either in utero or after birth. Methods: A retrospective review was performed of fetuses evaluated between 1996 and 2004 with the findings of irregular cardiac rhythm. 1st or 2nd degree AV block was diagnosed on Doppler and M-mode recordings, and confirmed using either fetal magnetocardiography (fMCG) or postnatal 12-lead ECG. Dexamethasone was administered to 4 mothers with abnormal fetal AV conduction in the setting of anti-Ro/anti-La antibodies. Results: Of 702 fetuses initially referred for arrhythmia, 306 had an irregular rhythm. Eight (2.6%) had intermittent 1st or 2nd degree AV block confirmed by fMCG and/or postnatal 12-lead ECG. AV block was presumed idiopathic in 2, associated with congenital long QT syndrome in 2 or with clinically unsuspected maternal anti-Ro or anti-La antibodies in 4. During the intrauterine period there was no progression to complete AV block and all were born alive at 34–40 weeks of gestation. Conclusion: A small but clinically significant population of fetuses with irregular rhythm will have 1st or 2nd degree AV block. Transplacental therapy may limit the intrauterine progression to more advanced disease.

An expanded phenotype of maternal SSA/SSB antibody-associated fetal cardiac disease

Objectives. Conventional manifestations of fetal Sjögrens antibodies (SSA/SSB) associated cardiac disease include atrioventricular block (AVB), transient sinus bradycardia, endocardial fibroelastosis (EFE) and dilated cardiomyopathy. We describe other manifestations of cardiac disease. Methods. We describe three fetuses with unique myocardial and conduction system disease. Results. One had isolated EFE with subsequent mitral and tricuspid valve chordal avulsion, the second had sinoatrial and infrahissian conduction system disease, and in both, neonatal progression to life threatening disease occurred. The third had sinus node dysfunction and atrial flutter. Conclusion. These findings expand the clinical phenotype of maternal SSA/SSB antibody associated fetal cardiac disease.

Complex atrial tachycardias and respiratory syncytial virus infections in infants.

Respiratory syncytial virus (RSV), a common cause of respiratory infections in children, has only rarely been associated with acquired heart disease. We reviewed hospital charts, rhythm strips, and electrocardiograms of 8 infants with abnormal supraventricular tachycardia (SVT), > 250 beats/min, associated with acute RSV infections. Cultures of nasopharyngeal specimens from six of eight infants grew RSV. Two infants with negative viral culture results had symptoms typical of an RSV infection during a documented RSV epidemic. Two infants had congenital heart defects. Seven of the eight infants had an ectopic atrial tachycardia, chaotic atrial tachycardia, or atrial flutter, and five of eight had episodes of nonsustained wide-complex SVT. One patient was initially treated with intravenously administered lidocaine for an incorrect diagnosis of ventricular tachycardia. SVT was unrelated to either beta-agonist therapy or hypoxic episodes. SVT did not recur after discharge in any infant with a structurally normal heart. Both patients with structural heart disease had recurrences of SVT. We conclude that RSV infections in infants may be associated with unusual atrial tachycardias and that the diagnosis may be complicated by episodes of nonsustained, wide-complex tachycardias. In patients with RSV and structurally normal hearts, chaotic and ectopic atrial tachycardias are self-limited and do not require prolonged drug therapy.

A management strategy for fetal immune-mediated atrioventricular block

Introduction. The purpose of this study is to describe an in utero management strategy for fetuses with immune-mediated 2° or 3° atrioventricular (AV) block. Methods and results. The management strategy as applied to 29 fetuses consisted of three parts. First, using fetal echocardiography and obstetrical ultrasound, we assessed fetal heart rate (FHR), heart failure, growth and a modified biophysical profile score (BPS) assessing fetal movement, breathing and tone. Second, we treated all fetuses with transplacental dexamethasone, adding terbutaline if the FHR was <56 bpm. Digoxin and/or intravenous immune globulin (IVIG) was added for progressive fetal heart failure. Third, we delivered fetuses by cesarean section for specific indications that included abnormal BPS, maternal/fetal conditions, progression of heart failure, or term pregnancy. We assessed perinatal survival, predictors of delivery and maternal/fetal complications in 29 fetuses with 3° (n = 23) or 2° (n = 6) AV block. There were no fetal deaths. In utero therapy included dexamethasone (n = 29), terbutaline (n = 13), digoxin (n = 3) and/or IVIG (n = 1). Delivery indications included term gestation (66%), fetal/maternal condition (14%), low BPS (10%) and progression of fetal heart failure (10%). An abnormal BPS correlated with urgent delivery. Conclusion. These results suggest that applying this specific management strategy that begins in utero can improve perinatal outcome of immune-mediated AV block.

Investigation of Near Ohmic Behavior for Poly(3,4-ethylenedioxythiophene): A Model Consistent with Systematic Variations in Polymerization Conditions

The impedance behavior of semiconducting polymer film electrodes based on poly(3,4-ethylenedioxythiophene) (PEDOT) in combination with a series of anionic dopants has been investigated using electrochemical impedance spectroscopy (EIS) over the frequency range from 0.1 Hz to 100 kHz. Films were electrodeposited on gold-coated Pt wire electrodes from a nonaqueous solution containing 3,4-ethylenedioxythiophene (EDOT). EIS results reveal that, under the optimal synthesis conditions, PEDOT electrodes consistently exhibit low, frequency-independent impedance over a wide frequency range (from ∼10 Hz to 100 kHz). These results suggest that the behavior originates from the two-layer homogeneous morphology of the film. A model for conduction in the films that is supported by experimental evidence is proposed, and EIS data for electrodes produced under a variety of electropolymerization conditions are presented.

Accelerometer Systolic Time Intervals as Fast-Response Sensors of Upright Posture in the Young

BACKGROUND Sensors of posture may improve rate-adaptive pacing in syndromes where syncope occurs in the upright posture, particularly in the young. No sensor of posture has been described to date. Previous studies suggest that two sensors currently under investigation (preejection period [PEP] and left ventricular ejection time [LVET] systolic time intervals [STIs] and accelerometers) may be affected by posture. A PEP-sensing pacemaker is available commercially in which heart rate (HR) decreases with an increase in PEP (delta(HR)/delta[PEP]< 0). In patients with upright syncope, it is not known how such algorithms respond to posture. Also, it is not known whether STIs correlate with posture independent of autonomic tone. METHODS AND RESULTS We studied accelerometer-derived STIs in head-upright tilt-testing with beta-blockade and catecholamine stimulation in patients with syncope or presyncope using an ultra-low-frequency accelerometer placed on the chest. Thirty-two patients age 6 to 22 years with unexplained recurrent syncope or presyncope underwent tilt-testing involving two to four tilts (60 degrees) at baseline, during esmolol infusion (500 micrograms/kg load, 50 to 140 micrograms/kg per minute), after esmolol withdrawal, and during isoproterenol infusion if not contraindicated. PEP, LVET, and other indexes were quantified, and their relations to posture and to autonomic state were determined. With tilt, PEP increased from 98.9 +/- 2.2 to 109.1 +/- 2.8 msec (P < .0001), and LVET decreased (supine-to-upright) from 295.5 +/- 4.5 to 247.2 +/- 4.7 msec (P < .0001). PEP/LVET changed from 0.337 +/- 0.01 to 0.45 +/- 0.02 (P < .0001). Similar postural changes were observed during tilt with beta-blockade and esmolol withdrawal, and during isoproterenol infusion. STI changes occurred immediately on postural change and were stable. Postural change of PEP was greater than the beta-adrenergic effect by 6:1. Postural change of STIs was independent of vagal tone. CONCLUSIONS First, accelerometer-derived STIs detect postural changes. Because these changes are independent of autonomic tone and are rapid and stable, they may be useful as fast-response sensors of upright posture in rate-adaptive pacemakers. Second, with postural change, HR increases when PEP increases. However, PEP-sensing pacemakers presently under investigation assume the opposite (inverse) mathematical relationship. Therefore, current PEP-sensing pacemakers use an incorrect algorithm for physiological postural responses in syncope patients. These data predict a paradoxical tachycardic response to the supine posture in patients implanted with these devices.

Covalent surface chemical modification of electrodes for cardiac pacing applications

We report the covalent surface modification of active-fixation pacemaker electrodes with butanethiol or dodecanethiol self-assembled monolayers (SAMs) using a platinum or gold metal-thiolate bond (i.e., changing the chemical identity of the exposed metal electrode from metal to organic) in such fashion that (a) the surface is organic in functionality with lipophilic physicochemical characteristics, (b) a possible degradation product is gold (I)-alkanethiolate with putative anti-inflammatory actions, and (c) current density/electric field strength is increased. Superior acute and chronic pacing performance with dodecanethiol-modified, gold-coated, platinum-iridium alloy pacemaker electrodes was observed with inferential evidence of reduced inflammation and scar. This approach may have applicability in other areas of bioelectrodes with practical applications in clinical cardiology, surgery, neuroscience, and subcutaneous sensors.

Esmolol tilt testing with esmolol withdrawal for the evaluation of syncope in the young.

BACKGROUND Head-upright tilt (HUT) testing is valuable in evaluating syncope. Isoproterenol is used to increase sensitivity. However, isoproterenol is contraindicated or dangerous in undiagnosed heart disease and produces false-positives. We introduced esmolol withdrawal during esmolol HUT, hypothesizing that (1) acute withdrawal of the ultrashort-acting beta-blocker induces beta-adrenergic effects by unmasking endogenous catecholamines and may provoke syncope with fewer risks, and (2) response to esmolol/esmolol withdrawal may predict effective therapy. METHODS AND RESULTS Thirty-six patients with unexplained recurrent syncope/presyncope (7 to 35 years old, known heart disease or arrhythmia in 14) underwent 2 to 4 HUT tests (60 degrees, 49 minutes): (1) baseline, (2) esmolol (500 micrograms/kg plus 50 micrograms.kg-1.min-1), (3) esmolol withdrawal (HUT continued after esmolol stopped), and (4) isoproterenol if tests 1 through 3 were negative and isoproterenol was not contraindicated. A positive test reproduced symptoms with hypotension or bradycardia, requiring recumbency for recovery. Twenty-five had positive tests, and 11 had negative tests. In 5, only the baseline test was positive; in 15, esmolol/esmolol withdrawal tests were also positive, with 3 in whom esmolol withdrawal was positive although negative at baseline. Two isoproterenol tilts were positive. Esmolol withdrawal and isoproterenol tilts had the highest initial heart rate and similar maximal heart rate increment. Only isoproterenol caused hypertension. One isoproterenol test was false-positive, with hypertension-induced arterial baroreflex. Treatment was beta-blockers (8), Na/fludrocortisone (9), both (6), and DDD pacemakers (2). Esmolol/esmolol withdrawal accurately predicted therapeutic response in 15; isoproterenol predicted therapeutic response in none. CONCLUSIONS Esmolol withdrawal tilt testing is preferable to isoproterenol for provocative testing of syncope in the young, and it appears to be safer. Esmolol withdrawal testing has clinical utility before invasive testing as a first-line investigation for syncope in patients with or without heart disease.