Dyslipidemia Among Adults With Congenital Heart Disease.

Background: Atherosclerotic disease is an important cause of morbidity among adults with congenital heart disease (CHD). Prevalence of dyslipidemia in this group is poorly described. Objectives: This study aimed to describe the prevalence of dyslipidemia among adults with CHD. Methods: A prospective, outpatient screening study was conducted among adults aged ≥18 years at 4 New England ambulatory congenital cardiology centers. Participants were surveyed regarding cardiovascular risk factors. Nonfasting fingerstick samples were obtained for analysis using a point-of-care lipid analyzer. Results: Lipid screening was completed on 186 participants (median age 30 [range 18-71] years, 50% female). Eighteen (10%) had simple CHD anatomy, and 63 (34%) had complex anatomy. Only 15% of 169 respondents reported history of high cholesterol. Eighty-five (46%) participants met National Cholesterol Education Program definition of dyslipidemia with 60 (32%), 62 (34%), and 37 (20%) having low high-density lipoprotein cholesterol (HDL-C <40 mg/dL), high non-HDL-C (≥130 mg/dL), and high total cholesterol (TC ≥200 mg/dL), respectively. TC was higher among participants with simple CHD than among those with moderate and complex lesions (mean 178.4 ± 48.7 vs 170.1 ± 35.0 vs 157.6 ± 34.5 mg/dL; P = 0.03). HDL-C was lower among participants with complex CHD than among those with simple and moderate lesions (mean 44.1 ± 13.5 vs 46.9 ± 12.5 vs 49.8 ± 15.3 mg/dL; P = 0.05). Conclusions: Dyslipidemia is highly prevalent among our cohort of adults with CHD, despite <15% reporting a prior diagnosis. Low HDL-C was more common in complex CHD, and high TC was more common in simple or moderate CHD. Lipid screening should be part of preventive health maintenance for all adults with CHD.

Noninvasive Electrocardiography in the Perinatal Mouse.

Electrocardiography (ECG) has long been relied upon as an effective and reliable method of assessing cardiovascular (and cardiopulmonary) function in both human and animal models of disease. Individual heart rate, rhythm, and regularity, combined with quantitative parameters collected from ECG, serve to assess the integrity of the cardiac conduction system as well as the integrated physiology of the cardiac cycle. This article provides a comprehensive description of the methods and techniques used to perform a noninvasive ECG on perinatal and neonatal mouse pups as early as the first postnatal day, without requiring the use of anesthetics. This protocol was designed to directly address a need for a standardized and repeatable method for obtaining ECG in newborn mice. From a translational perspective, this protocol proves to be entirely effective for characterization of congenital cardiopulmonary defects generated using transgenic mouse lines, and particularly for analysis of defects causing lethality at or during the first postnatal days. This protocol also aims to directly address a gap in the scientific literature to characterize and provide normative data associated with maturation of the early postnatal cardiac conduction system. This method is not limited to a specific postnatal timepoint, but rather allows for ECG data collection in neonatal mouse pups from birth to postnatal day 10 (P10), a window that is of critical importance for modeling human diseases in vivo, with particular emphasis on congenital heart disease (CHD).

Regional implementation of a pediatric cardiology chest pain guideline using SCAMPs methodology.

BACKGROUND AND OBJECTIVES: Chest pain is a complaint for which children are frequently evaluated. Cardiac causes are rarely found despite expenditure of considerable time and resources. We describe validation throughout New England of a clinical guideline for cost-effective evaluation of pediatric patients first seen by a cardiologist for chest pain using a unique methodology termed the Standardized Clinical Assessment and Management Plans (SCAMPs). METHODS: A total of 1016 ambulatory patients, ages 7 to 21 years initially seen for chest pain at Boston Children's Hospital (BCH) or the New England Congenital Cardiology Association (NECCA) practices, were evaluated by using a SCAMPs chest pain guideline. Findings were analyzed for diagnostic elements, patterns of care, and compliance with the guideline. Results from the NECCA practices were compared with those of Boston Children's Hospital, a regional core academic center. RESULTS: Two patients had chest pain due to a cardiac etiology, 1 with pericarditis and 1 with an anomalous coronary artery origin. Testing performed outside of guideline recommendations demonstrated only incidental findings. Patients returning for persistent symptoms did not have cardiac disease. The pattern of care for the NECCA practices and BCH differed minimally. CONCLUSIONS: By using SCAMPs methodology, we have demonstrated that chest pain in children is rarely caused by heart disease and can be evaluated in the ambulatory setting efficiently and effectively using minimal resources. The methodology can be implemented regionally across a wide range of clinical practice settings and its approach can overcome a number of barriers that often limit clinical practice guideline implementation.

Prevalence of noncardiac findings in patients undergoing cardiac magnetic resonance imaging.

PURPOSE: We sought to determine the prevalence of clinically significant non-cardiac abnormalities found in pediatric and adult patients undergoing cardiac magnetic resonance imaging (CMRI), and understand the impact of age on it's occurrence. METHODS: We retrospectively reviewed all patients undergoing CMRI between May 2004 and July 2007. Findings were considered significant if they required radiographic or clinical follow-up. RESULTS: A total of 408 patients underwent CMRI during the study period. Twenty two (16%) pediatric patients (age < 19 years, n = 135) were found to have a total of 22 non- cardiac abnormalities, 3 of which were clinically significant. Sixty four (23%) adult patients (age > 19 years, n = 273) were found to have a total of 77 non-cardiac abnormalities, 33 of which were clinically significant. The prevalence of clinically significant non-cardiac abnormalities was 2% in the pediatric cohort and 11% in the adult cohort (P = 0.05). Within the adult population, the prevalence of significant non-cardiac abnormalities increased with advancing age (P = 0.05). CONCLUSIONS: In a population of unselected patients undergoing CMRI, unanticipated noncardiac abnormalities were frequently seen. A small number of these were significant, with the prevalence increasing with age.

Improved accuracy in flow mapping of congenital heart disease using stationary phantom technique.

BACKGROUND: Flow mapping by cardiovascular magnetic resonance has become the gold standard for non-invasively defining cardiac output (CO), shunt flow and regurgitation. Previous reports have highlighted the presence of inherent errors in flow mapping that are improved with the use of a stationary phantom control. To our knowledge, these studies have only been performed in healthy volunteers. RESULTS: We analyzed the variation in flow measurements made with and without stationary phantom correction in 31 patients with congenital heart disease. Variation in stroke volume (SV) measurements was seen in all vessels across all patient groups. The variation was largest when analyzing the right ventricular outflow tract (RVOT), with a range of absolute differences in SV from 0.2 to 70 ml and in CO from 0.02 to 4.8 L/min. In patients with repaired Tetrology of Fallot (ToF), the average ratio of pulmonary to systemic blood flow (Qp:Qs) was 1.18 without and 1.02 with phantom correction. Without performing phantom correction, 23% of the repaired ToF patients were classified as having a residual shunt as compared to 0% when flow mapping was performed with phantom correction. Similarly, in patients with known atrial level shunting (ASD/PAPVR) 20% of patients had no shunt when flow mapping was performed without phantom correction as compared to 0% with phantom correction. In patients with bicuspid aortic valves (BAV), the differences in the regurgitant fraction between measuring flow with and without phantom correction ranged from 0 to 30%, while the regurgitant fraction in the RVOT of ToF patients varied by as much as 31%. CONCLUSION: The impact of inherent errors in CMR flow mapping should not be underestimated. While the variation across a population may not display a significant trend, for any individual patient it can be quite large. Failure to correct for such variation can lead to clinically significant misinterpretation of flow data. The use of the stationary phantom correction technique appears to improve accuracy both in normal patients as well as those with congenital heart disease.

Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium.

OBJECTIVE: Abnormal hemodynamic loading often accompanies congenital heart disease both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload. METHODS: Pressure-overload left ventricular hypertrophy was induced in 7- to 10-day-old rabbits by banding the thoracic aorta. Left ventricular function and mechanics were quantified by serial echocardiography and noninvasive left ventricular wall stress analysis. Left ventricular tissue sections were examined for fibrosis by using Masson's trichrome stain and for myocyte apoptosis by using a myocyte-specific DNA fragmentation assay and caspase-3 activation (specific fluorescent substrate). RESULTS: Significant myocyte apoptosis (198 +/- 37/10(6) myocytes, P < .01 vs control) and caspase-3 activation were present in early hypertrophy when left ventricular contractility was preserved and compensatory hypertrophy had normalized wall stress. By 6 weeks, multiple indices of left ventricular contractility were reduced, and left ventricular wall stress was increased. Myocyte apoptosis was accelerated (361 +/- 56/10(6) myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% +/- 4%. CONCLUSION: In experimental infant left ventricular hypertrophy, myocyte apoptosis is initiated in the face of normalized wall stress and preserved contractility. The ongoing rate of apoptosis causes a measurable decrease in myocyte number that is coincident with the onset of ventricular dysfunction. It thus appears that pressure overload, even at its earliest stages, is not well tolerated by the developing ventricle.

Intra-aortic balloon pump use in the failing Fontan circulation.

Acute cardiogenic shock in patients with Fontan physiology, while uncommon, is associated with devastating outcomes. Management of these patients is increasingly relying on the use of mechanical support. The use of intra-aortic balloon pump is underutilized. This report highlights the successful use of this modality in an adult with Fontan physiology and reviews the literature on this approach in such patients.

Left heart growth, function, and reintervention after balloon aortic valvuloplasty for neonatal aortic stenosis.

BACKGROUND: Transcatheter balloon aortic valvuloplasty (BAVP) has become the first-line treatment for critical aortic stenosis (AS) in neonates. However, little is known about the growth and function of left heart structures or about patterns of reintervention on the left heart after neonatal BAVP. METHODS AND RESULTS: Between 1985 and 2002, 113 patients underwent neonatal BAVP at < or =60 days of age. There were 16 early deaths (14%), with a significant decrease from 1985 to 1993 (22%) to 1994 to 2002 (4%), and 6 patients had successful early conversion to a univentricular circulation. In the short term, the mean relative gradient reduction was 54+/-26%, and significant aortic regurgitation (AR) developed in 15% of patients. The 91 early survivors with a biventricular circulation were followed up for 6.3+/-5.3 years, during which time there was a steady increase in the frequency of significant AR. Freedom from moderate or severe AR was 65% at 5 years. In almost all patients with a baseline aortic annulus z score less than -1, the annulus diameter increased to within the normal range within 1 to 2 years. Similarly, left ventricular (LV) end-diastolic dimension z scores, which ranged from -5 to 7.5 before BAVP, normalized within 1 to 2 years in nearly all patients with a predilation z score less than -1. Among early survivors with a biventricular circulation, reintervention-free survival on the LV outflow tract was 65% at 1 year and 48% at 5 years, with younger age, higher pre- and post-BAVP gradients, and a larger balloon-annulus diameter ratio associated with decreased reintervention-free survival (P<0.01). Seventeen surgical interventions were performed on the aortic valve in 15 patients, including replacement in 7. Survival free from aortic valve replacement was 84% at 5 years. CONCLUSIONS: BAVP for AS during the first 60 days of life results in short-term relief of AS in the majority of patients. Among early survivors, initially small left heart structures may be associated with worse subacute outcomes but typically normalize within 1 year. Reintervention for residual/recurrent AS or iatrogenic AR is relatively common, particularly during the first year after BAVP, but aortic valve replacement during early childhood is seldom necessary.

Recombinant human growth hormone treatment for dilated cardiomyopathy in children.

OBJECTIVE: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure among children and is often progressive despite maximal medical therapy. Heart failure is characterized by a number of neurohormonal abnormalities, including derangements in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling axis. Decreased serum levels of GH, which acts on cardiac myocytes primarily through IGF-1, are associated with impaired myocardial growth and function, which can be improved with restoration of GH/IGF-1 homeostasis. In animal models and among human adults with heart failure attributable to DCM, treatment with GH results in acquisition of left ventricular (LV) mass and improved LV function, through a combination of mechanisms. We undertook this study to determine the effects of recombinant human GH on LV function and mass among children with stable LV dysfunction attributable to DCM. METHODS: We performed a prospective, single-center, randomized, partially blinded, crossover trial among children 1 to 19 years of age with DCM and cardiac dysfunction of > or =6-month duration. After enrollment, patients were randomly assigned to receive treatment for 6 months with either conventional therapy (determined by the patient's primary cardiologist) plus recombinant human GH (0.025-0.04 mg/kg per day), administered as daily subcutaneous injections, or conventional therapy alone. Patients were then crossed over to the other treatment strategy for 6 months. The primary outcome measure was change in LV shortening fraction (SF). Other echocardiographic indices of LV function, somatic growth, and somatotropic/thyroid hormone levels were also monitored. RESULTS: Only 8 of an intended 15 patients were enrolled, because of a combination of factors. Two patients withdrew during the study as a result of declining LV function requiring transplantation. LV SF did not change significantly during GH treatment, although both LV SF and LV SF z score were higher 6 months after cessation of GH treatment than at baseline. LV ejection fraction increased during GH therapy to a degree that approached significance. Height and weight percentiles for age increased significantly during GH therapy and remained higher 6 months after treatment. Annualized height velocity during GH treatment (13.7 +/- 3.3 cm/year, >97th percentile for all patients) was significantly higher than that after GH discontinuation (3.2 +/- 3.5 cm/year). Serum levels of IGF-1 and IGF-binding protein-3 were significantly higher after 6 months of GH treatment and 6 months after discontinuation of GH treatment than at baseline. There were no adverse events related to GH treatment. DISCUSSION: In this prospective, single-center, randomized, partially blinded, crossover trial, recombinant human GH was administered to 8 pediatric patients with stable chronic heart failure secondary to DCM. Because of unanticipated difficulty enrolling eligible patients, the study was underpowered to detect changes in our primary outcome measure of the magnitude we projected. Nevertheless, we did observe several notable cardiovascular effects of GH treatment, including a trend toward improved LV ejection fraction during the course of GH treatment and significantly improved LV SF, SF z score, and LV end systolic stress z score 6 months after discontinuation of GH treatment (relative to baseline values). Given the fact that levels of IGF-1, the primary myocardial effector of GH signaling, remained significantly higher 6 months after GH treatment than at baseline, the improvement in LV functional indices 6 months after discontinuation of therapy may represent progression or perpetuation of a GH treatment effect. In addition to its cardiovascular effects, GH therapy was associated with significant acceleration of somatic growth. The benefits of GH were not associated with significant attributable side effects, although 2 patients developed progressive LV dysfunction during the study and underwent cardiac transplantation.

Promoting angiogenesis protects severely hypertrophied hearts from ischemic injury.

BACKGROUND: Myocardial hypertrophy is associated with progressive contractile dysfunction, increased vulnerability to ischemia-reperfusion injury, and is, therefore, a risk factor in cardiac surgery. During the progression of hypertrophy, a mismatch develops between the number of capillaries and cardiomyocytes per unit area, suggesting an increase in diffusion distance and the potential for limited supply of oxygen and nutrients. We hypothesized that promoting angiogenesis in hypertrophied hearts increases microvascular density, thereby improves tissue perfusion and substrate availability, maintains myocardial function, and improves postischemic recovery. METHODS: Left ventricular hypertrophy was created in 10-day-old rabbits by aortic banding and progression was monitored by echocardiography. At 4 weeks (compensated hypertrophy), 2 microg of vascular endothelial growth factor (VEGF) or placebo was administered intrapericardially. After 2 weeks, microvascular density, coronary flow (CF), and glucose uptake (GU) were measured. Tolerance to ischemia was determined by cardiac function measurements before and after ischemia-reperfusion using an isolated heart preparation. RESULTS: Microvascular density increased significantly following VEGF treatment (1.43 +/- 0.08/nuclei/field vs 1.04 +/- 0.06/nuclei/field untreated hypertrophy). Concomitantly, there was an increase in CF (7 +/- 0.5 vs 5 +/- 0.4 mL/min/g) and GU (1.24 +/- 0.2 vs 0.69 +/- 0.2 micromoles/g/30 minutes; p

Evidence of adverse ventricular interdependence in patients with atrial septal defects.

Right ventricular (RV) volume overload is associated with left ventricular (LV) distortion and dysfunction. The availability of transcatheter device closure of secundum atrial septal defect (ASD) provides an ideal model for investigating the immediate effects of elimination of RV volume overload and avoiding the confounding effects of surgery on LV function. Echocardiograms before and after device closure of ASD were analyzed for ejection fraction, percent changes in cross-sectional area and circumference, percent changes in free wall and septal endocardial lengths, and eccentricity. We enrolled 34 patients (median age 9 years) who underwent device closure of ASD (pulmonary to systemic shunt 1.6 +/- 0.4). Ejection fraction and LV end-diastolic volume, reflective of chamber preload, were significantly decreased in the presence of RV volume overload and normalized after defect closure with normalization of LV shape. Altered LV geometry secondary to RV volume overload was associated with regional variation in preload,such that diastolic circumference, a surrogate of myofiber preload, increased after closure of ASD secondary to a small increase in LV free wall arc length in conjunction with a much more significant increase in septal length. Thus, LV dysfunction associated with RV volume overload is secondary to altered chamber geometry and decreased myofiber preload. This physiology is immediately reversible and is independent of heart rate and afterload.

Clinical outcomes and utility of cardiac catheterization prior to superior cavopulmonary anastomosis.

OBJECTIVES: We sought to characterize the outcomes of routine catheterization prior to superior cavopulmonary anastomosis and to determine if some patients were unlikely to benefit from catheterization and thus might be evaluated preoperatively with noninvasive methods alone. BACKGROUND: Congenital heart disease patients with single ventricle physiology undergo routine echocardiography and cardiac catheterization prior to superior cavopulmonary anastomosis to determine anatomic and hemodynamic suitability for this procedure. METHODS: We performed a retrospective review of all infants (n = 114) evaluated for potential superior cavopulmonary anastomosis at our institution from January 1997 to June 2000. RESULTS: Patients' median age was 5.5 months. Full echocardiograms were obtained in 79 patients (69%). At catheterization a total of 41 interventions were performed in 35 patients (31%). Twenty-seven patients (24%) were transfused, 18 patients (17%) required cardiac intensive care unit admission, and median length of stay following catheterization was 1 day (range 0 to 22). Complications occurred in 28 patients (25%), most transient. Of 51 patients who had complete echocardiograms without indication for catheterization, none subsequently had significant interventions and only 2 had new findings at catheterization. Three candidates were excluded from operation; all 111 others underwent successful procedures and survived to hospital discharge. CONCLUSIONS: Interventions were frequent at catheterization prior to superior cavopulmonary anastomosis, but transient complications, transfusion, intensive care unit admission, and prolonged hospital length of stay were common. For patients in whom no issues indicating need for catheterization are identified by echocardiogram, routine catheterization rarely results in new information or intervention. These patients may be more safely evaluated preoperatively using exclusively noninvasive techniques.

Noninvasive serial evaluation of myocardial mechanics in pressure overload hypertrophy of rabbit myocardium.

BACKGROUND: The determination of progression from afterload mismatch to myocardial failure in small animals requires invasive monitoring to assess ventricular pressure. OBJECTIVE: We sought to (1) validate the noninvasive determination of blood pressure using optical plethysmography, and (2) determine the time course and progression from afterload mismatch to myocyte failure in neonatal rabbits with coarctation (aortic banding at 7-10 days of life) compared to normal rabbits. METHODS AND RESULTS: Comparison of continuous arterial pressure determined by optical plethysmography with high-fidelity intraarterial recording was performed in nine animals. An accuracy of 5.9 +/- 4.7 and 9.2 +/- 6.9 mm Hg for systolic and diastolic blood pressure was noted. Fourier analysis confirmed similar frequency components. Simultaneous transthoracic echocardiography and optical plethysmography were serially performed in 33 banded and 13 control animals. Load-dependent and -independent measures of myocardial function were obtained. Midwall contractility, initially normal, showed a gradual significant deterioration (0.22 +/- 1.68 [week 3] to -1.36 +/- 1.24 [week 6]; Z-scores). CONCLUSIONS: This novel noninvasive method for determination of myocardial mechanics allows for serial evaluation of cardiac function and the determination of the time course from compensated hypertrophy to myocyte failure.

Adaptive mechanisms of left ventricular diastolic function to the physiologic load of pregnancy.

BACKGROUND: Pregnancy is associated with marked alteration in cardiovascular hemodynamics. Recent reports have characterized the effects on cardiac systolic function. Little has been written on the influences of loading conditions on Doppler measures of diastolic function during pregnancy. HYPOTHESIS: Stage of pregnancy has an impact on Doppler indices of diastolic function independent of loading conditions, systolic function, and heart rate. METHOD: Thirty healthy women were prospectively evaluated by serial echocardiography and Doppler examinations at six time periods: 10-12, 18-20, 28-30, 36-38 weeks gestation, 2-4 and 12-14 weeks postpartum. The related effects on indices of diastolic function and its interaction with load, heart rate, mass, and systolic function were determined. RESULTS: Compared with the nonpregnant state, early (E) velocity increased (0.7+/-0.1-0.9+/-0.1 m/s, p = 0.0001), peaking at 18 weeks and returning to normal levels during late pregnancy. Atrial phase (A) velocity peaked at 18 weeks (0.48+/-0.12-0.60+/-0.13 m/s, p = 0.0001), remaining high throughout the rest of pregnancy. Consequently, the EWA ratio fell significantly during late pregnancy, from 1.9+/-0.4 to 1.4+/-0.3 (p = 0.02). In addition, mean acceleration was significantly increased in early pregnancy with a peak at 18 weeks (7.4+/-1.3 m/s2), returning to nonpregnant level at term (5.7+/-1.4 m/s2, p = 0.0001). Generalized estimating equation using multivariate regression analysis demonstrated that rising heart rate and stroke volume index had an independent effect on A velocity, and that contractility and preload had an independent effect on E velocity. Pregnancy itself had an independent influence on early filling, not explained by the other parameters. CONCLUSIONS: During normal pregnancy, there is a reversible shift in transmitral flow velocities from early to late filling with a decrease in acceleration, consistent with an increase in ventricular compliance. Changes in heart rate, preload, and contractility, as well as stage of pregnancy influence this alteration.

Outcome after reconstruction of discontinuous pulmonary arteries.

OBJECTIVE: This study was undertaken to determine outcomes of and optimal treatment strategies for reconstruction of congenital or acquired discontinuity of branch pulmonary arteries. METHODS: Between 1985 and 2000 pulmonary artery continuity was established in 102 patients with discontinuous central pulmonary arteries and normal peripheral arborization. Data were obtained retrospectively. RESULTS: Techniques to connect both pulmonary arteries included direct pulmonary artery-pulmonary artery anastomosis (n = 33), tube graft interposition (n = 47), or pulmonary arterial implantation in right ventricular-pulmonary arterial conduits (n = 22). Among patients with biventricular repair (n = 66), survival was 85% +/- 8% at 5 years, and freedom from surgical or interventional pulmonary arterioplasty was 31% +/- 11%. At most recent follow-up, mean branch pulmonary arterial z scores were -0.5 +/- 1.6 (right pulmonary artery) and -1.4 +/- 1.3 (left pulmonary artery). Mean right to left ventricular pressure ratio was 0.61 +/- 0.26, and this value was more than 0.75 in 13 of 58 cases. Fifteen of 51 had a lung perfusion mismatch of more than 75:25, and in 9 of 58 one branch pulmonary artery was occluded. Twenty-two patients who underwent primary establishment of antegrade pulmonary artery flow without previous shunt procedures had comparable survival and reintervention rates, with a tendency toward higher pulmonary arterial z scores and lower right to left ventricular pressure ratios. Among patients with single-ventricle repair (n = 33), 5-year survival was 93% +/- 8% and freedom from pulmonary arterioplasty was 39% +/- 9%. Ten of 19 patients had a lung perfusion mismatch, and one branch pulmonary artery was occluded in 4 of 31. Overall, a direct pulmonary artery anastomosis was associated with better survival (P =.006). The presence of aortopulmonary collaterals was a risk factor for pulmonary artery occlusion (P =.03). CONCLUSION: Good survival can be achieved for patients with pulmonary artery discontinuity, but this requires frequent reinterventions. Direct pulmonary artery- pulmonary artery anastomoses and control of all collateral vessels may further improve outcome.