Adam L. Dorfman

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis

Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy

ABSTRACT Class IA phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110α catalytic subunit of class IA PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class IA PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85α regulatory subunit and germ line deletion of the p85β regulatory subunit of class IA PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class IA PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.

Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.

ABSTRACT Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1−/−, S6K2−/−, and S6K1−/− S6K2−/− mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.

Use of Medical Imaging Procedures With Ionizing Radiation in Children: A Population-Based Study

OBJECTIVE To determine population-based rates of the use of diagnostic imaging procedures with ionizing radiation in children, stratified by age and sex. DESIGN Retrospective cohort analysis. SETTING All settings using imaging procedures with ionizing radiation. PATIENTS Individuals younger than 18 years, alive, and continuously enrolled in UnitedHealthcare between January 1, 2005, and December 31, 2007, in 5 large US health care markets. MAIN OUTCOME MEASURES Number and type of diagnostic imaging procedures using ionizing radiation in children. RESULTS A total of 355 088 children were identified; 436 711 imaging procedures using ionizing radiation were performed in 150 930 patients (42.5%). The highest rates of use were in children older than 10 years, with frequent use in infants younger than 2 years as well. Plain radiography accounted for 84.7% of imaging procedures performed. Computed tomographic scans-associated with substantially higher doses of radiation-were commonly used, accounting for 11.9% of all procedures during the study period. Overall, 7.9% of children received at least 1 computed tomographic scan and 3.5% received 2 or more, with computed tomographic scans of the head being the most frequent. CONCLUSIONS Exposure to ionizing radiation from medical diagnostic imaging procedures may occur frequently among children. Efforts to optimize and ensure appropriate use of these procedures in the pediatric population should be encouraged.

Characterization of cardiac tumors in children by cardiovascular magnetic resonance imaging: a multicenter experience.

OBJECTIVES The aim of this study was to report the results of an international multicenter experience of cardiac magnetic resonance imaging (MRI) evaluation of cardiac tumors in children, each with histology correlation or a diagnosis of tuberous sclerosis, and to determine which characteristics are predictive of tumor type. BACKGROUND Individual centers have relatively little experience with diagnostic imaging of cardiac tumors in children, because of their low prevalence. The accuracy of cardiac MRI diagnosis on the basis of a pre-defined set of criteria has not been tested. METHODS An international group of pediatric cardiac imaging centers was solicited for case contribution. Inclusion criteria comprised: 1) age at diagnosis ≤18 years; 2) cardiac MRI evaluation of cardiac tumor; and 3) histologic diagnosis or diagnosis of tuberous sclerosis. Data from the cardiac MRI images were analyzed for mass characteristics. On the basis of pre-defined cardiac MRI criteria derived from published data, 3 blinded investigators determined tumor type, and their consensus diagnoses were compared with histologic diagnoses. RESULTS Cases (n = 78) submitted from 15 centers in 4 countries had the following diagnoses: fibroma (n = 30), rhabdomyoma (n = 14), malignant tumor (n = 12), hemangioma (n = 9), thrombus (n = 4), myxoma (n = 3), teratoma (n = 2), and paraganglioma, pericardial cyst, Purkinje cell tumor, and papillary fibroelastoma (n = 1, each). Reviewers who were blinded to the histologic diagnoses correctly diagnosed 97% of the cases but included a differential diagnosis in 42%. Better image quality grade and more complete examination were associated with higher diagnostic accuracy. CONCLUSIONS Cardiac MRI can predict the likely tumor type in the majority of children with a cardiac mass. A comprehensive imaging protocol is essential for accurate diagnosis. However, histologic diagnosis remains the gold standard, and in some cases malignancy cannot be definitively excluded on the basis of cardiac MRI images alone.

Surgical outcome for patients with the mitral stenosis–aortic atresia variant of hypoplastic left heart syndrome

OBJECTIVE We sought to identify and characterize a subgroup of patients with hypoplastic left heart syndrome who might be at higher risk for stage I failure. METHODS From January 2001 through December 2006, all patients with hypoplastic left heart syndrome who underwent stage I palliation at Childrens Hospital Boston were retrospectively reviewed. The subgroup with the mitral stenosis-aortic atresia variant was studied separately. We evaluated preoperative echocardiographic data, operative characteristics, and postoperative factors associated with death or the need for transplantation. The Kaplan-Meier method was used to assess survival. RESULTS Thirty-eight (23%) of 165 patients had mitral stenosis-aortic atresia. Hospital mortality or need for transplantation for patients with mitral stenosis-aortic atresia was significantly higher than for other anatomic subgroups (29% vs 7.9%, P = .002). Left ventricle-subepicardial coronary artery communications were present in 20 (53%) patients with mitral stenosis-aortic atresia and were associated with a significantly higher hospital mortality (50% vs 6%, P = .004). No difference in outcome was demonstrated between different sources of pulmonary blood flow. A longer cardiopulmonary bypass time (P = .02) and the need for postoperative extracorporeal membrane oxygenation support (P < .001) were associated with a higher mortality rate. CONCLUSIONS With improved outcomes in the management of neonates with hypoplastic left heart syndrome, those with the mitral stenosis-aortic atresia variant and left ventricle-subepicardial coronary artery fistulae have emerged as a higher-risk subgroup for failure of stage I palliation. Further investigation is required, and a change in clinical management strategy for this particular subgroup might be warranted.

Magnetic resonance imaging evaluation of congenital heart disease: conotruncal anomalies.

Conotruncal anomalies comprise a diverse group of congenital heart defects involving the outflow tracts of the heart and the great vessels, including tetralogy of Fallot, transposition of the great arteries, truncus arteriosus, interrupted aortic arch, and other anomalies. Cardiovascular magnetic resonance (CMR) imaging plays an increasingly important role in the evaluation of patients with these lesions. Advances in CMR allow comprehensive assessment of cardiovascular anatomy, ventricular function, flow, and myocardial perfusion and viability. This article reviews the clinical aspects and the application of CMR before and after surgery in key conotruncal anomalies.

Relation of Right Ventricular Dilation, Age of Repair, and Restrictive Right Ventricular Physiology With Patient-Reported Quality of Life in Adolescents and Adults With Repaired Tetralogy of Fallot

The present study aimed to determine the predictors of patient-reported quality of life and restrictive right ventricular (RV) physiology in adolescents and adults with repaired tetralogy of Fallot. A total of 62 patients (median age 28.5 years, range 14 to 69) undergoing cardiovascular magnetic resonance imaging completed the Short Form 36-item questionnaire, version 2, a validated quality of life assessment. RV inflow curves were generated from the sum of tricuspid inflow and pulmonary insufficiency. The patient-reported quality of life was comparable to population norms. Patients repaired after 1 year of age showed a strong trend toward a greater likelihood of physical component summary age-adjusted z-score ≤-1 (odds ratio 7.50, 95% confidence interval 0.90 to 62.3, p = 0.06). Patients with a RV ejection fraction of <45% reported decreased physical component summary (p = 0.02) and physical functioning (p = 0.02) scores. The RV end-diastolic volume, pulmonary regurgitation, and diastolic indexes did not predict the quality of life. The indexed RV end-diastolic volume was related to diastolic abnormalities, correlating with a greater peak early filling rate (r = 0.71, p <0.0001), ratio of peak early to atrial filling rates (r = 0.45, p = 0.006), and showing a strong trend with the end-diastolic forward flow in the pulmonary trunk (odds ratio 2.67 for moderate dilation and 3.50 for severe dilation, p = 0.06). Patients who underwent repair before 1 year old were more likely to have end-diastolic forward flow (15 of 17 vs 25 of 42, p = 0.03). In conclusion, the RV ejection fraction and age of repair were the best predictors of quality of life in this population, in whom end-diastolic forward flow and associated diastolic parameters appeared to reflect an overdistended ventricle, which might suggest a role for early pulmonary valve replacement.

An integrated approach to patient-specific predictive modeling for single ventricle heart palliation

In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient-specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre-operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient-specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi-scale modeling.

Reproducibility of Echocardiographic Diagnosis of Left Ventricular Noncompaction

BACKGROUND Left ventricular noncompaction (LVNC) cardiomyopathy is variably defined by numerous trabeculations, deep intertrabecular recesses, and noncompacted-to-compacted (NC/C) ratio >2. Limited studies exist on the reproducibility of diagnosing LVNC. METHODS Clinical records of patients diagnosed with LVNC by echocardiography were reviewed. Blinded review of the index echocardiogram for all patients and a 1:1 match without LVNC was performed independently by two observers, measuring the number of trabeculations and the NC/C ratio. RESULTS A total of 104 patients with LVNC were included in the study, 52 with no congenital heart disease (NCongHD) and 52 with congenital heart disease (CongHD). The duration of follow-up was 7.2 years (range, 0.5-23.1 years) for NCongHD and 8.2 years (range, 0-33.3 years) for CongHD. Agreement between observers in determining zero to three versus more than three trabeculations was 59% (NCongHD) and 73% (CongHD). Agreement in measuring an NC/C ratio ≤ 2 versus > 2 was 79% (NCongHD) and 74% (CongHD). Agreement with the original reader in diagnosing LVNC was 67%. There was no association between the number of trabeculations or the NC/C ratio and the likelihood of a major event. Patients with moderate or severe left ventricular dysfunction at the time of diagnosis were more likely to undergo cardiac transplantation or die compared with those with normal or mild dysfunction (NCongHD, 22% vs 0%, P = .01; CongHD, 39% vs 3%, P = .001). CONCLUSIONS The reproducibility of making measurements to diagnose LVNC by accepted criteria is poor. Heart transplantation and death are associated with significant ventricular dysfunction and not with increased trabeculations or NC/C ratios.