Ventricular septal defect.

Ventricular septal defects account for up to 40% of all congenital cardiac malformations. The diagnosis encompasses a broad range of anomalies, including isolated defects and those associated with other congenital cardiac malformations. Presentation, symptoms, natural history, and management of ventricular septal defects depend on size and anatomical associations of the anomaly, patient's age, and local diagnostic and interventional expertise. In this Seminar, we describe the anatomical range of ventricular septal defects and discuss present management of these malformations. Genetic determinants, diagnostic techniques, physiological considerations, and management challenges are examined in detail. Unfortunately, in many circumstances, evidence on which to guide optimum management is scarce. We present some longer term considerations of ventricular septal defects in adolescents and adults, with particular emphasis on patients with raised pulmonary vascular resistance and Eisenmenger's syndrome.

Accuracy of knowledge-based reconstruction for measurement of right ventricular volume and function in patients with tetralogy of Fallot.

We tested the accuracy and reproducibility of knowledge-based reconstruction (KBR) for measuring right ventricular (RV) volume and function. KBR enables rapid assessment of the right ventricle from sparse user input by referencing a database. KBR generates a 3-dimensional surface to fit points that the user enters at anatomic landmarks. We measured the RV volume using KBR from magnetic resonance images in 20 patients with repaired tetralogy of Fallot at end-diastole and end-systole. We entered points in the long- and short-axis and/or oblique views. The true volume was computed by manually tracing the RV borders for 3-dimensional reconstruction using the piecewise smooth subdivision surface method. The reference database included 54 patients with tetralogy of Fallot patients. The KBR values agreed closely with the true values for the end-diastolic volume (r = 0.993), end-systolic volume (r = 0.992), and ejection fraction (EF; r = 0.930). KBR slightly overestimated the end-diastolic volume (4 +/- 10 ml, p = NS), end-systolic volume (1 +/- 9 ml, p = NS), and EF (4 +/- 3%, p = NS). No bias in the error was found by Bland-Altman analysis (p = NS for end-diastolic and end-systolic volume and EF). The KBR volumes had approached the true volumes (235 +/- 93 vs 243 +/- 93, p = 0.012, r = 0.978 for end-diastolic and end-systolic volumes combined) already after the first run and the entry of 19 +/- 3 points. In conclusion, KBR provided accurate measurement of the RV volume and EF with minimal user input. KBR is a clinically feasible alternative to full manual tracing of the heart borders from imaging data.

LAMP2 microdeletions in patients with Danon disease.

BACKGROUND: Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated. METHODS AND RESULTS: We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5'-untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)(n) simple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2. CONCLUSIONS: This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.

Short-term mechanical unloading and reverse remodeling of failing hearts in children.

BACKGROUND: Mechanical support using a left ventricular assist device (LVAD) can lead to functional recovery of the myocardium in patients with end-stage heart failure (HF). Molecular remodeling, cytoskeletal disruption, and apoptosis activation are associated with abnormal gene expression in the failing ventricular myocardium of HF subjects and can normalize in response to medium- and long-term mechanical unloading in adults. However, there is little knowledge of the changes in gene expression after short-term mechanical support in children with HF. METHODS: We evaluated left ventricular biopsies from 4 children with HF. The children had implantation of a continuous- or a pulsatile-flow LVAD for 8 to 16 days before undergoing heart transplantation. At the time of LVAD insertion and removal, we performed quantitative real-time polymerase chain reaction (QPCR) to study the expression of 326 genes encoding for structural, transcriptional, and signaling pathways proteins, and immunoblot analysis on dystrophin and apoptotic factors. RESULTS: Short-term LVAD therapy significantly decreased brain natriuretic peptide (BNP) levels from pre-LVAD (3,584.5 +/- 378.3 pg/ml [95% CI]) to post-LVAD (447.5 +/- 52.7 pg/ml [95% CI]) in 2 patients in whom comparative BNP measurements were available. In addition, short-term LVAD therapy reduced HF and apoptosis markers, whereas it upregulated structural proteins, including dystrophin, as well as pro-hypertrophic and pro-inotropic markers. Furthermore, LVAD therapy normalized expression of genes involved in calcium homeostasis, cell growth, and differentiation. CONCLUSIONS: Our pilot study suggests that even short-term LVAD therapy in children with severe HF can reverse molecular remodeling. This favorable effect should be taken into consideration in eligible children with significant ventricular dysfunction.

Correlation of right ventricular ejection fraction and tricuspid annular plane systolic excursion in tetralogy of Fallot by magnetic resonance imaging.

The correlation between right ventricular ejection fraction (RVEF) and tricuspid annular plane systolic excursion (TAPSE) by two-dimensional (2-D) echo has been repeatedly validated, but not by magnetic resonance imaging (MRI) nor in patients with congenital heart disease. We tested whether TAPSE measurements by MRI correlate with RVEF in surgically repaired tetralogy of Fallot (TOF) patients. TAPSE was measured from systolic displacement of the RV-freewall/tricuspid annular plane junction in the apical 4-chamber view in 7 normal subjects and 14 TOF patients. The RV was reconstructed in 3-D from manually traced borders on MR images to compute true EF. Because we previously observed discrepancy between TAPSE and RVEF in the presence of regional dysfunction, we also analyzed RV wall motion in terms of regional stroke volume at 20 short axis slices from apex to tricuspid annulus. RVEF was 52 +/- 3% in normal subjects and 41 +/- 9% in TOF (P < 0.01). TAPSE correlated weakly (r = 0.50, P < 0.05) with RVEF. TOF patients exhibited increased regional stroke volume from apical portions of the RV and decreased regional stroke volume at the base compared to normal (P < 0.05 at 15 of 20 slices). Regional stroke volume in apical slices correlated inversely with RVEF such that patients with higher apical stroke volume had lower RVEF (P < 0.05). TAPSE is not a reliable measure of RVEF in TOF by MRI. TAPSE may be of limited use in conditions that exhibit abnormal regional contraction.

Three-dimensional shape analysis of right ventricular remodeling in repaired tetralogy of Fallot.

Understanding of right ventricular (RV) remodeling is needed to elucidate the mechanism of RV dysfunction in the overloaded right ventricle, but is hampered by the chamber's complex shape. We imaged 15 patients with repaired tetralogy of Fallot (TOF) and 8 normal subjects by magnetic resonance imaging in long- and short-axis views. We reconstructed the right ventricles in 3 dimensions using the piecewise smooth subdivision surface method. Shape was analyzed from cross-sectional contours generated by intersecting the right ventricle with 20 planes evenly spaced from apex to tricuspid annulus. Patients with TOF had dilated right ventricles compared with normal (end-diastolic volume index 216 +/- 99 vs 81 +/- 16 ml/m(2), p <0.001) but near-normal function (ejection fraction 40 +/- 9% vs 48 +/- 12%, respectively, p = NS). RV shape in patients with TOF differed from normal subjects in several ways. First, the right ventricle had a larger normalized cross-sectional area in patients with TOF (p <0.01 in apical planes). Second, the cross-sectional shape was rounder in patients with TOF (p <0.05 in apical planes). Also, the interventricular septum underwent relatively less enlargement so that it comprised only 27 +/- 4% of total RV surface area in patients with TOF, compared with 33 +/- 2% in normal subjects (p = 0.0001). In addition, the right ventricle in patients with TOF exhibited bulging basal to the tricuspid valve (4 +/- 4% of total RV length), unlike normals (1 +/- 2%, p <0.001). This basal bulging was amplified by tilting of the tricuspid annulus (29 +/- 11 degrees vs 15 +/- 7 degrees , respectively, p <0.005). In conclusion, the right ventricle remodels in several directions rather than following a shape continuum. Characterization of RV remodeling from 3-dimensional reconstructions provides novel insights.

MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.

Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in approximately 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone and three families with TAAD/PDA, we identified novel mutations in two families with TAAD/PDA, but none in families with TAAD alone. Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. SMC hyperplasia leading to significant lumen narrowing in some of the vessels of the adventitia was also observed. Insulin-like growth factor-1 (IGF-1) was upregulated in mutant aortas as well as explanted SMCs, but no increase in transforming growth factor-beta expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1alpha and beta) were also found. These data suggest that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and result in a distinct aortic and occlusive vascular pathology potentially driven by IGF-1 and Ang II.

Anomalous right coronary artery from the pulmonary artery: noninvasive diagnosis and serial evaluation.

Isolated anomalous origin of the right coronary artery from the main pulmonary artery (ARCAPA) is a rare congenital cardiac malformation. We reviewed the current literature and found only 31 patients with ARCAPA. We report the first case that was diagnosed and followed on a noninvasive basis with cardiovascular magnetic resonance after surgical re-implantation. This report of a patient with ARCAPA showed resolving coronary artery sizes secondary to decreased pulmonary steal. Cardiovascular magnetic resonance is an accurate and reliable imaging modality that allows serial noninvasive follow up in patients with coronary artery anomalies.

Quantitation and localization of matrix metalloproteinases and their inhibitors in human carotid endarterectomy tissues.

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a central role in arterial wall remodeling, affecting stability of fibrous caps covering atherosclerotic plaques. The objective of this study was to determine the spatial distribution of TIMP mass and MMP mass and activity of carotid endarterectomy (CEA) tissues and relate it to the distribution of atherosclerotic lesions. METHODS AND RESULTS: Fresh CEA tissues were imaged by multicontrast MRI to generate 3D reconstructions. Tissue segments were cut transversely from the common, bifurcation, internal, and external regions. Segments were subjected to total protein extractions and analyzed by ELISA for MMP-2 and -9 and TIMP-1 and -2 mass and by zymography for gelatinase activity. Segments at or near the bifurcation with highly calcified lesions contained higher MMP levels and activity than segments distant from the bifurcation; highly fibrotic or necrotic plaque contained lower MMP levels and activity and higher TIMP levels. Fatty streak, fibroatheroma with hemorrhage and calcification, and fully occluded lesions were enriched in MMP-2, MMP-9, and TIMP-1 and TIMP-2, respectively. CONCLUSIONS: The spatial distribution of MMPs and TIMPs in carotid atherosclerotic lesions is highly heterogeneous, reflecting lesion location, size, and composition. This study provides the first semi-quantitative maps of differential distribution of MMPs and TIMPs over atherosclerotic plaques.

Usefulness of real-time navigator magnetic resonance imaging for evaluating coronary artery origins in pediatric patients.

Navigator coronary magnetic resonance imaging (MRI) was evaluated in assessing coronary artery origins in a pediatric and adolescent population. Sixty-five consecutive infants, children, or adolescents (age range 11 days to 21 years) were referred for MRI evaluations to assess coronary artery origins. Coronary artery origins were unambiguously delineated in 62 of 65 patients. In 3 patients, irregular arrhythmias precluded cardiac gating of the magnetic resonance acquisition. Two patients had anomalous coronary artery origins detected. Twenty-six patients required sedation for the studies. Free-breathing 3-dimensional MRI with real-time navigator correction is a robust method for delineating the coronary artery origins in pediatric and adolescent patients.

Tracking regression and progression of atherosclerosis in human carotid arteries using high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) can accurately and reproducibly measure the volume of atherosclerotic plaque in human carotid arteries. Atherosclerotic plaques may either progress or regress over time, depending on individual risk factors and treatment regimens. This study was designed to determine if regression or progression of human carotid atherosclerosis in patients receiving statin therapy over 24 months can be detected by high-resolution MRI. METHODS: In 11 subjects who had undergone unilateral carotid endarterectomy and were on statin therapy, volumes for total carotid artery, concentric wall (normal wall), eccentric wall (plaque), and lumen were quantified at 0, 16 and 24 months using a 1.5-T human imager equipped with 6-cm phased array coils. RESULTS: The interobserver mean coefficient of variation (CV) was lowest for the lumen volume (3.1%) and highest for the plaque volume (9.8%). The interscan mean CV was lowest for the total artery volume (3.2%) and highest for the plaque volume (9.9%). As much as 26% regression and 35% progression were observed in individual subject's carotid artery eccentric wall (plaque) volumes over time. Mean eccentric wall volume increased 5% by 16 months and 8% by 24 months. Mean total wall volume increased slightly at both 16 and 24 months (+1.2% and +1.8%). CONCLUSIONS: High-resolution MRI provides a noninvasive reproducible method of tracking changes in carotid atherosclerosis. This pilot study detected changes in individual subjects at both 16 and 24 months. MRI tracking of changes in atherosclerotic plaques should prove useful in assessing vascular disease risk and monitoring the efficacy of interventions designed to induce regression or retard progression.

Role of echocardiography versus MRI for the diagnosis of congenital heart disease.

During the last few decades, significant strides have been made in the field of noninvasive imaging for the patient with congenital heart disease. Echocardiography and MRI continue to provide improved means of anatomic and functional assessment in children and adults with congenital heart lesions. This review reports some of the recent advances in tissue Doppler, strain rate, and integrated backscatter, and highlights exciting current and future potential developments in their application. We also discuss advances in MR in evaluation of cardiac anatomy and function in congenital heart disease.

Meandering right pulmonary vein to the left atrium and inferior vena cava: the first case with associated anomalies.

We report a case of a healthy, asymptomatic 6-year-old boy in whom an anomalous right pulmonary vein was noted to drain into both the inferior vena cava and left atrium in association with findings consistent with scimitar syndrome. The anomalous pulmonary vein took a very circuitous route through the lungs before draining into the left atrium, a condition previously termed "meandering pulmonary vein." To aid in the diagnosis, cardiovascular magnetic resonance imaging and magnetic resonance angiography were used to delineate this complex course and the connection of the anomalous pulmonary vein. To our knowledge, this is the 1st reported case of a meandering pulmonary vein with dual drainage to the inferior vena cava and left atrium in association with other anomalies.

Bilateral symmetry of human carotid artery atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis is a principal cause of stroke and myocardial infarction. The carotid arteries provide a site at which progression of atherosclerosis can be monitored reproducibly and noninvasively. This study was conducted to determine the similarity of atherosclerotic plaques in the left and right carotid arteries. This question was explored with the use of perfusion-fixed cadaveric carotid arteries and 2 noninvasive clinical imaging techniques, MRI and electron-beam CT. METHODS: Fifty pairs of carotid arteries from cadaveric donors (aged 48 to 98 years) were imaged with MRI and electron-beam CT. Thirty-eight of the pairs met the criteria for rigorous analysis. Carotid artery wall volumes were measured from the MRI images, and calcification scores were computed from the electron-beam CT images. RESULTS: Total wall volumes of the left (972.5+/-241.6 mm3) and right (1016.3+/-275.0 mm3) carotid arteries were moderately correlated (concordance correlation coefficient [r(c)]=0.71). Calcification scores were highly correlated, with r(c)=0.95 for the Agatston scores and r(c)=0.94 for the calcium volume scores. CONCLUSIONS: Total wall volume and plaque calcification in the left and right human carotid arteries are substantially similar. These results suggest that atherosclerosis of the human carotid arteries is generally a bilaterally symmetrical disease. This evidence of symmetry suggests that diagnostic information about atherosclerotic plaque in one carotid artery can be used to infer information about the composition and volume of atherosclerotic plaque in the contralateral artery.