Julie S. Glickstein

Fetal cardiac function assessed by Doppler myocardial performance index (Tei Index)

The Tei Index (TI) is a useful, non‐invasive, Doppler‐derived myocardial performance tool which can be used to assess aspects of systolic and diastolic function. The aim of this study was to determine normal values of fetal left ventricular (LV) TI in second‐ and third‐ trimester fetuses and to compare these to other values reported in the literature.

Cardiac Effects of Antiretroviral Therapy in HIV-Negative Infants Born to HIV-Positive Mothers: NHLBI CHAART-1 (National Heart, Lung, and Blood Institute Cardiovascular Status of HAART Therapy in HIV-Exposed Infants and Children Cohort Study)

OBJECTIVES The aim of this study was to investigate the possible effects of antiretroviral therapy (ART) in utero on cardiac development and function in human immunodeficiency virus (HIV)-negative children. BACKGROUND ART reduces vertical HIV transmission. Long-term cardiotoxicity after in utero exposure to ART is unknown in children but has occurred in young animals. METHODS Using a prospective multisite cohort study design, echocardiograms taken between birth and 24 months were compared in 2 groups of HIV-negative infants of HIV-positive mothers: 136 infants exposed to ART (ART+) and 216 unexposed infants (ART-). RESULTS Mean left ventricular (LV) mass z-scores were consistently lower in ART+ girls than in ART- girls: differences in mean z-scores were -0.46 at birth (p = 0.005), -1.02 at 6 months (p < 0.001), -0.74 at 12 months (p < 0.001), and -0.79 at 24 months (p < 0.001). Corresponding differences in z-scores for boys were smaller: 0.13 at 1 month (p = 0.42), -0.44 at 6 months (p = 0.01), -0.15 at 12 months (p = 0.37), and -0.21 at 24 months (p = 0.21). Septal wall thickness and LV dimension were smaller than expected in ART+ infants, but LV contractility was consistently about 1 SD higher at all ages (p < 0.001). In ART+ infants, LV fractional shortening was higher than in ART- infants; girls showed a greater difference. CONCLUSIONS Fetal exposure to ART is associated with reduced LV mass, LV dimension, and septal wall thickness z-scores and increased LV fractional shortening and contractility up to age 2 years. These effects are more pronounced in girls than in boys. Fetal ART exposure may impair myocardial growth while improving depressed LV function.

Abnormalities of the corrected QT interval in familial dysautonomia: An indicator of autonomic dysfunction

We report abnormalities in corrected QT intervals with changes in position and after exercise in patients with familial dysautonomia and confirm the previously reported finding of abnormal heart rate and blood pressure responses. Prolonged corrected QT intervals (> 440 msec) with lack of appropriate shortening with exercise is a noninvasive means of demonstrating an aberration in autonomic regulation of cardiac conduction.

The fetal Doppler mechanical PR interval: A validation study

Objective: To evaluate the accuracy of pulsed Doppler-derived fetal PR interval measurements obtained by physicians participating in a multicenter prospective fetal echocardiographic study. Methods: Echocardiograms on healthy fetuses were performed and evaluated by 15 pediatric cardiologists/perinatologists across the United States who are participating in a larger clinical trial involving fetuses at risk for autoantibody-associated congenital heart block. Prior to enrolling women in the main trial, each physician was provided with a teaching tape to demonstrate how the pulsed Doppler-derived PR interval is measured. The procedure involves placing a gated pulsed Doppler sample volume in the left ventricle at the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract in an apical 5-chamber view, and simultaneously obtaining left ventricular filling and emptying. Time intervals are measured from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole). This represents the mechanical PR interval. Each physician measured the pulsed Doppler-derived fetal PR interval on 5 different subjects recruited from the physician’s specific site. To validate each physician’s technique, the tapes were sent to a central facility and the same intervals were remeasured by an experienced central reader (D.M.F.). A physician was determined to have adequate ability to measure the fetal PR interval if all 5 measurements were within ± 30 ms of the central reader’s measurements, where 30 ms corresponds to 25% of the mean observed in normative PR interval data. This difference was deemed to be the minimum clinically important difference in Doppler PR interval. Results: Fourteen of the 15 physicians were considered to have adequate ability to measure the fetal PR interval according to our established criterion. The overall mean difference between the physicians and the central reader’s measurements was –0.26 ± 11.04 ms (p = 0.84). In addition, 95% of the observed differences were included in the interval (–22.23 to 21.81), which is well within our clinically acceptable range of ± 30 ms. Conclusions: The pulsed Doppler assessment of the mechanical PR interval in the fetus can be accurately performed after minimal training. This technique may be a valuable tool for identification of early and potentially reversible conduction abnormalities in fetuses at risk for more advanced and permanent forms of heart block associated with maternal antibodies to SSA/Ro-SSB/La.

Referral for fetal echocardiography is associated with increased maternal anxiety

Background. Referral for fetal echocardiography (fECHO) is an acute stressor that may induce significant maternal anxiety. To promote good clinical management of expectant mothers in this situation, including adequate screening for possible psychiatric interventions, data are needed regarding the psychosocial functioning of women scheduled for fECHO procedures. Objective. To investigate the association between fECHO and maternal anxiety. Methods. Pregnant women answered two questionnaires before first fECHO. The Spielberger State-Trait Anxiety Inventory (STAI) assessed how subjects feel “now” (state) versus how they “usually feel” (trait). Separate state and trait anxiety scores were calculated; scores were compared between the study cohort and a gestational age-matched historical cohort of 31 pregnant women who did not undergo fECHO. A second questionnaire developed by the investigators ascertained pregnancy specific concerns and characteristics. Results. Forty subjects were enrolled. The mean state score of the fECHO cohort (42.1 ± 15.1) differed from the historical cohort (32.8 ± 11.3; p = 0.006); however there was no difference between trait scores (34.7 ± 10.8 vs. 35.4 ± 12.8; p = 0.8). A multivariate linear regression model controlling for race and maternal age demonstrated that fECHO was a strong independent predictor of maternal state anxiety score (p = 0.004, β = 10.4). Conclusions. Pregnant women presenting for fECHO report high anxiety levels compared with women not presenting for fECHO. Clinician awareness and sensitivity are recommended and further investigation of modifiers of anxiety in this high risk group should be explored.

Congenital heart block in neonatal lupus: The pediatric cardiologist’s perspective

Clinical presentation. Congenital heart block (CHB) in the absence of major structural abnormalities is associated with maternal antibodies to Ro (SS-A) and La (SS-B). CHB is most commonly diagnosed between 18 and 24 wk of gestation, and may be first, second or third degree (complete). Mortality approaches ∼20%, and most surviving children require pacemakers. Affected infants may develop cardiomyopathy. Abnormalities in the skin, liver and blood of neonates are also associated with anti-Ro/La antibodies, and are usually self-limiting; these manifestations and CHB are collectively referred to as neonatal lupus syndromes (NLS).Investigation of pathogenesis. Recent studies demonstrate that Ro/La ribonucleoproteins appear on the surface of apoptotic fetal cardiocytes and are recognized by their cognate antibodies, promoting an inflammatory response. Mice immunized with Ro/La proteins have offspring with conduction abnormalities.In vitro, human serum and IgG with anti-Ro/La antibodies affect the conducting properties of isolated animal heart tissue.Diagnostic problems. If fetal bradycardia is identified, a 2-dimensional and M-mode fetal echocardiographic and Doppler ultrasound should be obtained to determine whether there is an atrial arrhythmia or atrioventricular (AV) block, and to what degree, and whether there are major structural abnormalities of the heart. The mother’s serum should be tested by ELISA for anti-Ro and/or anti-La antibodies.Therapeutic options. To date, only anecdotal and retrospective evidence guidesin utero therapy of CHB. A prospective trial is currently underway to evaluate the efficacy of maternal oral dexamethasone in treating newly identified first, second or third degree block. Established third-degree block appears to be irreversible. Dexamethasone and sympathomimetics may be of some benefit in treating hydrops fetalis. In pregnant women with anti-Ro/La antibodies, prophylactic therapy is not indicated but serial echocardiographic analysis is strongly recommended, with emphasis on the mechanical PR interval to identify a reversible block.Conclusion. CHB occurs in ∼1–5% of pregnancies in mothers with antiRo/La antibodies, independent of the mother’s disease status, and in ∼15–20% of pregnancies following the birth of a child with NLS. Treatment of CHB identifiedin utero is not established but guidelines are provided. Serial echocardiographic monitoring of high-risk pregnancies, using the mechanical PR interval to identify first degree block, may afford the earliest opportunities for therapeutic intervention

Preliminary observations on the use of midodrine in treating orthostatic hypotension in familial dysautonomia

Midodrine, a peripheral alpha-adrenergic agonist, was evaluated in 7 female and 2 male patients with familial dysautonomia (FD), a disorder characterized by decreased sympathetic innervation. Prior to and after three months of midodrine treatment, each patients response to postural change was assessed by arteriosonde readings of blood pressure and heart rate, corrected QT-interval measurements, Doppler evaluation of renal blood flow and circulating atrial natriuretic peptide (ANP) levels. The initial midodrine dose (2.5 mg three times daily) was raised until subjective symptoms improved. Doses were reduced if patients felt jittery or developed erect hypertension (systolic > 180 mmHg or diastolic > 110 mmHg). Midodrine, at an average dose of 0.25 mg/kg per day, improved subjective symptoms in all patients. With treatment, magnitude of blood pressure responses was variable. Although mean erect blood pressure did not increase significantly for the aggregate, it did increase in six of nine patients. In addition, the QTc interval normalized and erect renal perfusion improved. Changes in supine mean blood pressure and supine circulating ANP correlated directly. We judge midodrine to be useful in management of orthostatic hypotension in patients with familial dysautonomia.

Parents of children with congenital heart disease prefer more information than cardiologists provide

OBJECTIVES To determine whether pediatric cardiologists and parents of older children with congenital heart disease (CHD) share similar expectations regarding the education and counseling that should be provided to parents of children with CHD in both the prenatal and neonatal period. DESIGN Consenting parents of older children with CHD (age >3 years) and cardiologists ranked the importance of education topics on a scale of 1 (unimportant) to 10 (very important). The rankings of parents and cardiologists were compared using Students t-test. RESULTS We had 38 cardiologists and 41 parents complete the questionnaire. There was a statistically significant difference in rankings between cardiologist and parents of children with CHD (P<0.03). Parents consistently ranked topics as more important than cardiologists with a mean difference in rank score of 0.85 ±0.3. In the prenatal period, the most significant differences between parents and cardiologists were noted for information related to the childs quality of life. For neonatal counseling, the most significant differences were noted for information regarding follow-up care and the parents ability to describe the childs CHD to medical personnel. CONCLUSION Parents of older children with CHD would prefer to receive more counseling and education in the prenatal and newborn period than cardiologists perceive is wanted.

Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction

Objective: Electrocardiographic repolarization intervals were evaluated to determine the extent of cardiac autonomic dysfunction in patients with familial dysautonomia (FD) and to determine if any of these intervals could serve as a possible predicotr of clinical symptoms.Methods: Thirty-seven electrocardiograms of patients with FD were retrospectively evaluated. QT, JT, rate-corrected QT and JT intervals were calculated as well as QT and QTC dispersion. Results were compared to normative data and electrocardiograms of 20 age-matched control subjects.Observations: In the FD group, prolongation of QTC(>450 msec) was noted in 5/37 (13.5%) patients, as compared to 0/20 normal controls (p=NS), and prolongation of JTc (>340 msec) in 16/37 (43.3%) patients, as compared to 0/20 normal controls (p<0.001). QT and QTC dispersion were abnormal in 3/37 (8.1%) and 5/37 (13.5%), respectively. In the 16 FD patients with prolonged JTc, six had a positive history of syncope, whereas none of the 21 with normal JTc had syncope or symptoms suggesting arrhythmia (p<0.003). The positive predictive value of having syncope or symptoms suggestive of arrhythmia with an abnormal JTc is 37.5% (95% CI [15%, 65%]). The negative predictive value is 100% (95% CI [87%, 100%]).Conclusion: In the FD population, the electrocardiographic measure of repolarization that was most frequently abnormal was the JTc interval. Prolongation of the JTc interval was significantly more frequent than prolongation of the QTC interval (p<0.001) QT and QTC dispersions were less significantly affected in the FD population, indicating uniform ventricular recovery time. These results suggest that a prolonged JTc interval may be a more sensitive indicator of abnormal ventricular repolarization and cardiac autonomic dysfunction. Due to the known sympathetic denervation inherent in patients with FD, they are at risk for unopposed parasympathetic predominance. FD patients, therefore, are more likely to have brady arrhythmias and asystole rather than polymorphic ventricular tachycardia. The increased incidence of syncope in patients with prolonged JTc suggests that this measure may serve as a helpful marker to predict which FD patients are at increased risk of serious clinical sequelae including bradyarrhythmias with asystole or sudden death.

Cardiac Effects of Antiretroviral Therapy in HIV-Negative Infants Born to HIV-Positive Mothers

OBJECTIVES The aim of this study was to investigate the possible effects of antiretroviral therapy (ART) in utero on cardiac development and function in human immunodeficiency virus (HIV)-negative children. BACKGROUND ART reduces vertical HIV transmission. Long-term cardiotoxicity after in utero exposure to ART is unknown in children but has occurred in young animals. METHODS Using a prospective multisite cohort study design, echocardiograms taken between birth and 24 months were compared in 2 groups of HIV-negative infants of HIV-positive mothers: 136 infants exposed to ART (ART+) and 216 unexposed infants (ART-). RESULTS Mean left ventricular (LV) mass z-scores were consistently lower in ART+ girls than in ART- girls: differences in mean z-scores were -0.46 at birth (p = 0.005), -1.02 at 6 months (p < 0.001), -0.74 at 12 months (p < 0.001), and -0.79 at 24 months (p < 0.001). Corresponding differences in z-scores for boys were smaller: 0.13 at 1 month (p = 0.42), -0.44 at 6 months (p = 0.01), -0.15 at 12 months (p = 0.37), and -0.21 at 24 months (p = 0.21). Septal wall thickness and LV dimension were smaller than expected in ART+ infants, but LV contractility was consistently about 1 SD higher at all ages (p < 0.001). In ART+ infants, LV fractional shortening was higher than in ART- infants; girls showed a greater difference. CONCLUSIONS Fetal exposure to ART is associated with reduced LV mass, LV dimension, and septal wall thickness z-scores and increased LV fractional shortening and contractility up to age 2 years. These effects are more pronounced in girls than in boys. Fetal ART exposure may impair myocardial growth while improving depressed LV function.