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.

The potential utility of (123)I-mIBG in atrial fibrillation and in the electrophysiology laboratory.

A novel indication for (123)I-mIBG has recently been proposed to risk stratify patients with atrial fibrillation. This review puts into perspective the utility and importance of such a risk stratification modality, in the setting of the epidemic of atrial fibrillation, which also relates to the prevalence of heart failure, obesity, hypertension, and stroke. The authors argue that the epic cost of care for patients with paroxysmal and more advanced forms of atrial fibrillation-including catheter ablation, heart failure, and stroke management-coupled with the poor efficacy of all treatment modalities in advanced atrial fibrillation, make necessary a paradigm shift where only paroxysmal atrial fibrillation that demonstrably will turn into permanent fibrillation should be targeted aggressively. If this premise is accepted, then (123)I-mIBG nuclear imaging for risk stratification becomes a vital tool for the care of the individual patient, as well as for disease control and cost containment in the population, since (123)I-mIBG scanning alone can predict (with hazard ratios of the order of 3.0-5.0) the future occurrence of permanent atrial fibrillation or heart failure.

Atrial and ventricular rate response and patterns of heart rate acceleration during maternal-fetal terbutaline treatment of fetal complete heart block.

Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates or patterns of heart rate (HR) acceleration. Fetal atrial and ventricular beat rates were compared before and after transplacental terbutaline treatment (10 to 30 mg/day) by fetal echocardiography in 17 fetuses with CHB caused by immune-mediated damage to a normal conduction system (isoimmune, n = 8) or a congenitally malformed conduction system associated with left atrial isomerism (LAI, n = 9). While receiving terbutaline, 9 of the 17 fetuses underwent fetal magnetocardiography (fMCG) to assess maternal HR and rhythm, patterns of fetal HR acceleration, and correlation between fetal atrial and ventricular accelerations (i.e., AV correlation). Maternal HR and fetal atrial and ventricular beat rates increased with terbutaline. However, terbutaline's effects were greater on the atrial pacemaker(s) in fetuses with isoimmune CHB and greater on the ventricular pacemaker(s) in those with LAI-associated CHB. Patterns of fetal HR acceleration also differed between isoimmune and LAI CHB. Finally, despite increasing HR, terbutaline did not restore the normal coordinated response between atrial and ventricular accelerations in isoimmune or LAI CHB. In conclusion, the pathophysiologic heterogeneity of CHB is reflected in the differing effect of terbutaline on the atrial and ventricular pacemaker(s) and varying patterns of HR acceleration. However, regardless of the cause of CHB, terbutaline augments HR but not AV correlation, suggesting that its effects are determined by the conduction system defect rather than the autonomic control of the developing heart.

Ultrasonic biophysical measurements in the normal human fetus for optimal design of the monolithic fetal pacemaker.

Ultrasound measurements, including xiphoid-to-pericardial distance and deployment angle, were made on human fetuses as a function of gestational age for the purpose of assessing the likelihood of 3 failure modes of a monolithic fetal pacemaker, including primary positioning failure due to device length and secondary dislodgement failure due to somatic growth. The small variation of the measurements over the gestational age range relevant to device implantation for the major indications of the device (for complete heart block complicated by hydrops and for bradycardia risk after fetal surgery or intrauterine intervention) predicts a small likelihood of these failure modes.

In vivo CH3(CH2)11SAu SAM electrodes in the beating heart: in situ analytical studies relevant to pacemakers and interstitial biosensors.

To study in vivo modification of the SAM equivalent circuit when a highly ordered SAM is used as a bioelectrode, dodecanethiolate SAM-Au intramuscular electrodes were studied in living rat heart in a challenging in situ perfused rat model by impedance spectroscopy, cyclic voltammetry, and neutron activation analysis (NAA). The SAM layer experienced disintegration in vivo biological system, as NAA detected the presence of Au atoms that had leached into the surrounding living tissue. Therefore, the underlying Au surface became exposed during biological implant. Study by impedance spectroscopy, however, revealed perfect capacitive behavior for the SAM, similar to in vitro behavior. Electrodes showed a pure capacitive Nyquist plot with 86.1-89.4 degrees near-vertical line segments as the equivalent circuit locus, as for a parallel plate capacitor. Impedance magnitude varied linearly with 1/omega excluding diffusionally limited ionic charge transport. There was no diffusional conductive element Z(W infinity ) or spatially confined Warburg impedance Z(D). The effect of in vivo exposure of a highly ordered SAM is a 'sealing over' effect of new defects by the binding of proteinaceous or lipid species in the biological milieu, a fact of significance for SAM electrodes used either as pacemaker electrodes or as a platform for in vivo biosensors.

Chronic fatigue syndrome and eating disorders: concurrence or coincidence?

In this report we present four patients who were found to have both an eating disorder and the chronic fatigue syndrome (CFS). Two of the patients presented for evaluation of an eating disorder and also had CFS, while two of the patients presented for evaluation of CFS and also had an eating disorder. In all four patients the eating disorder preceded the CFS. We consider the question of whether the occurrence of these two disorders in the same patients is merely a coincidence; whether an eating disorder can act as a precipitant for CFS, perhaps through the exacerbation of an underlying vascular instability; and whether overlapping etiologies may predispose some adolescents to develop both disorders. We also discuss similarities (including diagnostic dilemmas, cultural influences, psychological correlates, demographic similarities, perceptual biases, and cardiovascular effects) encountered in the management of both of these disorders.

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.

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.

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

OBJECTIVES: Conventional manifestations of fetal Sjogren's 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.

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.

Defibrillator for primary prevention in congenital heart disease.

A 21-year-old patient with repaired double-outlet right ventricle and normal ventricular function underwent internal cardioverter defibrillator implantation for primary prevention of sudden death. First occurrence of spontaneous ventricular tachycardia resulted in hemodynamic collapse and syncope but the internal cardioverter defibrillator rescued the patient. ICD implantation for primary prevention may be an appropriate goal in adults with repaired congenital heart disease, even in the setting or normal ventricular function.

Determination of standard electrode potential E(o) for chronic platinum and gold electrodes in rat muscle: implications for biosensors and the "anode" of bipolar pacing.

Pacemaker electrode surface modification by organosilane and organic self-assembled monolayer strategies creates a possible new variable in pacemaker electrode behavior. Because all of these chemical surface coatings are unstable at extremes of potential, the potential to which the electrode relaxes (between pacing pulses) becomes extremely important. The authors measured this potential for platinum (Pt) and gold (Au) relevant for their use as anode (or cathode) in a bipolar pacing system and from this potential the standard electrode potential, E(o) was determined. Thirty-Four determinations were made by a null current three-electrode potentiostatic technique of 2.45 mm2 platinum or gold electrodes implanted chronically in blood perfused muscle in a spontaneously breathing rat. Linear voltage sweeps were performed while monitoring current with voltage at null current determined repeatedly at varying scan rates and limits. Electrode potential varied between -388 +/- 19 mV (vs Ag/Ag+) for platinum and -388 +/- 55 mV for gold electrodes. Hysteresis was observed in all sweeps (P < 0.008, Fisher's exact) and measured 61 +/- 17 mV (anodic) and 25 +/- 3 mV (cathodic) with steep dependence on polarity (P < 0.001, t-test). The findings were independent of the materials' electronic work function. E(o) versus normal hydrogen electrode (NHE) were thus -166 mV (platinum) and -166 mV (gold). Because the most common bipolar system, uses platinum as anode, these results are directly applicable to current pacing technology. Provided low thresholds are achievable with novel surface modified electrodes, the small range of variation of E(o), and the particular mean value observed, are both compatible with function, provided care is used during electrode testing to avoid surface disruption. These results are significant also for biosensors that use similar surface modification methodologies.

The monolithic fetal pacemaker: prototype lead design for closed thorax deployment.

Prenatal sudden cardiac death and hydrops fetalis are often due to complete heart block. However, no pacing modality exists for intrauterine application for fetal bradycardia. A prototype lead for a novel fetal pacemaker has been developed and used in a direct pacing model. It has been demonstrated that the lead can be safely and successfully deployed using a hypochondriac and transdiaphragmatic or subxiphoid approach. Pacing with ventricular capture was evident with the widening of QRS duration from 50.2 +/- 9.8 to 95.1 +/- 12.8 ms (P = 0.0001). Further studies by echocardiogram revealed an increase in the pulse with pacing, confirming pacing. This study documents proof-of-concept for closed thorax over-the-wire deployment of a novel lead design applicable to fetal pacing. By combining the lead design with microcircuitry and a small power source, it is possible to create a monolithic fetal pacemaker system capable of being deployed in utero.