Impact of reduction in right ventricular pressure and/or volume overload by percutaneous pulmonary valve implantation on biventricular response to exercise: an exercise stress real-time CMR study.

AIMS: To assess the impact of relief of pulmonary stenosis (PS) and pulmonary regurgitation (PR) by percutaneous pulmonary valve implantation (PPVI) on biventricular function during exercise stress. METHODS AND RESULTS: Seventeen patients, who underwent PPVI for PS or PR, were included. Magnetic resonance imaging was performed at rest and during supine exercise stress pre- and within 1-month post-PPVI, using a radial k - t SENSE real-time sequence. In patients with PS (n = 9), there was no reserve in right ventricular (RV) ejection fraction (EF) in response to exercise prior to PPVI (48.2 ± 12.1% at rest vs. 48.4 ± 14.8% during exercise, P = 0.87). Post-PPVI, reserve in RVEF in response to exercise was re-established (53.4 ± 15.0% at rest vs. 59.6 ± 17.3% during exercise, P = 0.003) with improvement in left ventricular stroke volume (LVSV) (45.4 ± 6.2 mL/m(2) at rest vs. 52.8 ± 8.8 mL/m(2) during exercise, P = 0.001). In patients with PR prior to PPVI (n = 8), LVSV during exercise increased (43.0 ± 8.5 vs. 54.3 ± 6.6 mL/m(2), P < 0.001) due to reduction in PR fraction during exercise (29.2 ± 5.2 vs. 13.6 ± 6.1%, P < 0.001). After PPVI, LVSV increased from rest to exercise (48.4 ± 8.8 vs. 57.2 ± 8.1 mL/m(2), P < 0.001) due to improved RVEF (45.5 ± 8.3 vs. 50.4 ± 6.9%, P = 0.001). There was a significantly higher increase in LVSV at exercise from pre- to post-PPVI in PS patients than in PR patients (ΔLVSV 8.2 ± 4.1 vs. Δ2.9 ± 4.1 mL/m(2), P = 0.01). The reduction in the RV outflow tract gradient correlated significantly with the improvement in LVSV during exercise (r = -0.73, P < 0.001). CONCLUSION: Percutaneous pulmonary valve implantation in patients with PS leads to restoration of reserve in RVEF during exercise stress. In patients with PR, SV augmentation improves only mildly post-PPVI. Improvement in SV augmentation during exercise stress after PPVI is dependent mainly on afterload reduction.

Cardiac outcomes in adults with supravalvar aortic stenosis.

AIMS: Supravalvar aortic stenosis is a rare form of left ventricular outflow tract obstruction that is often progressive in childhood. Little data are available on outcomes in the adult population. Our aim was to define cardiac outcomes in adults with supravalvar aortic stenosis. METHODS AND RESULTS: This is a multicentre retrospective study of cardiac outcomes in adults (≥18 years) with supravalvar aortic stenosis. We examined: (i) adverse cardiac events (cardiovascular death, myocardial infarction, stroke, heart failure, sustained arrhythmias, and infective endocarditis) and (ii) the need for cardiac surgery in adulthood. One hundred and thirteen adults (median age at first visit 19 years; 55% with Williams-Beuren syndrome; 67% with surgical repair in childhood) were identified. Adults without Williams-Beuren syndrome had more severe supravalvar aortic stenosis and more often associated left ventricular outflow tract obstructions (P < 0.001). In contrast, mitral valve regurgitation was more common in patients with Williams-Beuren syndrome. Eighty-five per cent of adults (96/113) had serial follow-up information (median follow-up 6.0 years). Of these patients, 13% (12/96) had an adverse cardiac event and 13% (12/96) had cardiac operations (7 valve repair or replacements, 4 supravalvar aortic stenosis repairs, 1 other). Cardiac surgery was more common in adults without Williams-Beuren syndrome (P = 0.007). Progression of supravalvar aortic stenosis during adulthood was rare. CONCLUSION: Adults with supravalvar aortic stenosis remain at risk for cardiac complications and reoperations, while progression of supravalvar aortic stenosis in adulthood is rare. Valve surgery is the most common indication for cardiac surgery in adulthood.

Quantification of biventricular myocardial function using cardiac magnetic resonance feature tracking, endocardial border delineation and echocardiographic speckle tracking in patients with repaired tetralogy of Fallot and healthy controls.

BACKGROUND: Parameters of myocardial deformation have been suggested to be superior to conventional measures of ventricular function in patients with tetralogy of Fallot (ToF), but have required non-routine, tagged cardiovascular magnetic resonance (CMR) techniques. We assessed biventricular myocardial function using CMR cine-based feature tracking (FT) and compared it to speckle tracking echocardiography (STE) and to simple endocardial border delineation (EBD). In addition, the relation between parameters of myocardial deformation and clinical parameters was assessed. METHODS: Overall, 28 consecutive adult patients with repaired ToF (age 40.4 ± 13.3 years) underwent standard steady-state-free precession sequence CMR, echocardiography, and cardiopulmonary exercise testing. In addition, 25 healthy subjects served as controls. Myocardial deformation was assessed by CMR based FT (TomTec Diogenes software), CMR based EBD (using custom written software) and STE (TomTec Cardiac Performance Analysis software). RESULTS: Feature tracking was feasible in all subjects. A close agreement was found between measures of global left (LV) and right ventricular (RV) global strain. Interobserver agreement for FT and STE was similar for longitudinal LV global strain, but FT showed better inter-observer reproducibility than STE for circumferential or radial LV and longitudinal RV global strain. Reproducibility of regional strain on FT was, however, poor. The relative systolic length change of the endocardial border measured by EBD yielded similar results to FT global strain. Clinically, biventricular longitudinal strain on FT was reduced compared to controls (P < 0.0001) and was related to the number of previous cardiac operations. In addition, FT derived RV strain was related to exercise capacity and VE/VCO2-slope. CONCLUSIONS: Although neither the inter-study reproducibility nor accuracy of FT software were investigated, and its inter-observer reproducibility for regional strain calculation was poor, its calculations of global systolic strain showed similar or better inter-oberver reproducibility than those by STE, and could be applied across RV image regions inaccessible to echo. 'Global strain' calculated by EBD gave similar results to FT. Measurements made using FT related to exercise tolerance in ToF patients suggesting that the approach could have clinical relevance and deserves further study.

Pregnancy outcome and management of women with an implantable cardioverter defibrillator: a single centre experience.

AIMS: With improved survival of patients with congenital and inherited heart disease, there is now a younger cohort of patients with an implantable cardioverter defibrillator (ICD) for the prevention and treatment of ventricular dysrrhythmias. Young women with such disorders often wish to embark on pregnancy, but pregnancy outcome data for this group is sparse. We therefore evaluated pregnancy outcome in patients with heart disease and an ICD in situ. METHODS AND RESULTS: A retrospective analysis was performed on all women with an ICD in situ, who had pregnancy care provided by the specialist maternal cardiology service at University College London Hospitals. Data for 19 pregnancies in 14 women were collected. The underlying cardiac diagnoses were congenital heart disease (one), familial hypertrophic cardiomyopathy (eight), familial dilated cardiomyopathy (one), inherited long QT syndrome (one), and idiopathic cardiac arrest (one). Three women had moderate impairment of the left ventricular systolic function (ejection fraction <45%), in the remainder it was normal. Nine ICD implants were for primary prevention of sudden cardiac death (64%) and five for secondary prevention (36%). Of the 19 pregnancies, 18 continued beyond 24 weeks gestation with 18 live births. In eight pregnancies there were medical or device-related complications (42.9%) as follows: arrhythmias (four) (21.1%), heart failure (two) (9.1%), ICD shocks (one) (5.3%), atrial lead fracture (one) (5.3%), and lead-related thrombus (one) (5.3%). There were no inappropriate device shocks or therapies. CONCLUSIONS: Women with heart disease and an ICD implant can have a good outcome during pregnancy but medical and device complications are not uncommon.

Cardiovascular magnetic resonance findings in repaired anomalous left coronary artery to pulmonary artery connection (ALCAPA).

BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare coronary artery anomaly. This study shows the role of cardiovascular magnetic resonance (CMR) in assessing young patients following surgical repair of ALCAPA. METHODS: 6 patients, aged 9-21 years, with repaired ALCAPA (2 Tackeuchi method, 4 direct re-implantation) underwent CMR because of clinical suspicion of myocardial ischemia. Imaging used short and long axis cine images (assess ventricular function), late-gadolinium enhancement (LGE) (detect segmental myocardial fibrosis), adenosine stress perfusion (detect reversible ischaemia) and 3D whole-heart imaging (visualize proximal coronary arteries). RESULTS: The left ventricular (LV) global systolic function was preserved in all patients (mean LV ejection fraction = 62.7% ± 4.23%). The LV volumes were within the normal ranges, (mean indexed LVEDV = 75.4 ± 3.5 ml/m², LVESV = 31.6 ± 9.4 ml/m²). In 1 patient, hypokinesia of the anterior segments was visualized. Five patients showed sub-endocardial LGE involving the basal, antero-lateral wall and the anterior papillary muscle. Three patients had areas of reversible ischemia. In these 3, 3D whole-heart MRA showed that the proximal course of the left coronary artery was occluded (confirmed with cardiac catheterisation). CONCLUSIONS: CMR is a good, non-invasive, radiation-free investigation in the post-surgical evaluation of ALCAPA. In referred patients we show that basal, antero-lateral sub-endocardial myocardial fibrosis is a characteristic finding. Furthermore, stress adenosine CMR perfusion, can identify reversible ischemia in this group, and was indicative of left coronary artery occlusion.

Mutations in sarcomere protein genes in left ventricular noncompaction.

BACKGROUND: Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. METHODS AND RESULTS: Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. CONCLUSIONS: We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Role of endogenous Fas (CD95/Apo-1) ligand in balloon-induced apoptosis, inflammation, and neointima formation.

BACKGROUND: Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown. METHODS AND RESULTS: To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (P<0.05; n=5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (P<0.05; n=6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (P<0.05; n=4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (P<0.05; n=6). Together with enhanced proliferation (bromodeoxyuridine index; P<0.05), these events resulted in a further increase in medial and neointimal cells (P<0.01; n=8) with thickened neointima in gld mice (intima/media ratio, x3.8 of WT; P<0.01). CONCLUSIONS: Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.

Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin.

Current imaging modalities of human atherosclerosis, such as angiography, ultrasound, and computed tomography, visualize plaque morphology. However, methods that provide insight into plaque biology using molecular tools are still insufficient. The extra-domain B (ED-B) is inserted into the fibronectin molecule by alternative splicing during angiogenesis and tissue remodeling but is virtually undetectable in normal adult tissues. Angiogenesis and tissue repair are also hallmarks of advanced plaques. For imaging atherosclerotic plaques, the human antibody L19 (specific against ED-B) and a negative control antibody were labeled with radioiodine or infrared fluorophores and injected intravenously into atherosclerotic apolipoprotein E-null (ApoE-/-) or normal wild-type mice. Aortas isolated 4 hours, 24 hours, and 3 days after injection exhibited a selective and stable uptake of L19 when using radiographic or fluorescent imaging. L19 binding was confined to the plaques as assessed by fat staining. Comparisons between fat staining and autoradiographies 24 hours after 125I-labeled L19 revealed a significant correlation (r=0.89; P<0.0001). Minimal antibody uptake was observed in normal vessels from wild-type mice receiving the L19 antibody and in atherosclerotic vessels from ApoE-/- mice receiving the negative control antibody. Immunohistochemical studies revealed increased expression of ED-B not only in murine but also in human plaques, in which it was found predominantly around vasa vasorum and plaque matrix. In summary, we demonstrate selective targeting of atheromas in mice using the human antibody to the ED-B domain of fibronectin. Thus, our findings may set the stage for antibody-based molecular imaging of atherosclerotic plaques in the intact organism.

Adhesion of monocytes to medical steel as used for vascular stents is mediated by the integrin receptor Mac-1 (CD11b/CD18; alphaM beta2) and can be inhibited by semiconductor coating.

Implantation of stents into stenosed arteries helps to restore normal blood flow in ischemic organs. However, limited biocompatibility of the applied medical steel can cause acute thrombosis and long-term restenosis. Adhesion of monocytes to stent metal may participate in those acute and long-term complications of stent placement. Based on described prominent electrochemical properties of the interaction between the monocyte integrin receptor Mac-1 and its various ligands, we hypothesized, that this receptor is a central mediator of monocyte adhesion to stent metal and that semiconductor coating of medical steel reduces monocyte adhesion. Adhesion of monocytes on L-316 stainless steel was directly evaluated by light microscopy. Mac-1 could be identified as mediator of monocyte adhesion, since cell adhesion could be blocked by anti-Mac-1-antibodies, including the cross-reacting anti-GPIIb/IIIa antibody fragment abciximab. To further prove the central role of Mac-1, two CHO cell lines were generated expressing recombinant Mac-1 either as wild type, resulting in a low affinity receptor, or mutant with a GFFKR deletion of the alpha(M) subunit, resulting in a high affinity receptor. Indeed, adhesion was specific for Mac-1 and dependent on the affinity state of this integrin. Finally, we could demonstrate that Mac-1-mediated adhesion of monocytes to stents can be significantly inhibited by silicon carbide coating of the stent metal. In conclusion, the integrin Mac-1 and its affinity state could be identified as major mediators of monocyte adhesion on medical steel. As therapeutic strategies, the blockade of Mac-1 by antibodies or silicon carbide coating of steel inhibits monocyte adhesion on stents.

Value of speckle-tracking echocardiography and MRI-based feature tracking analysis in adult patients after Fontan-type palliation.

BACKGROUND: Patients are commonly affected by ventricular dysfunction and heart failure after Fontan palliation. Reliable quantification of ventricular function is of interest but hampered by complex ventricular anatomy and physiology. OBJECTIVES: We aimed to assess myocardial function using a novel cardiac magnetic resonance imaging (CMR)-based feature-tracking (FT) technique and to study its clinical utility in Fontan patients. METHODS: Retrospective study in consecutive patients attending our service. RESULTS: We included 15 adult Fontan patients (age 27 ± 7 years) who underwent a standardized transthoracic echocardiographic investigation (TTE) with measurement of global strain using speckle tracking. Thirteen patients also underwent CMR, with assessment of myocardial deformation by FT, providing longitudinal and circumferential global strain for the single ventricle. The value of TTE-based strain measurements was limited by the fact that in 63% of patients at least one myocardial segment could not be adequately quantified due to limited acoustic windows. In contrast, CMR allowed for a complete visualization of all wall segments. Not surprisingly, there was poor agreement between the techniques but good or moderate interobserver variability for FT (coefficients of variability 6.6% and 14.3% for circumferential and longitudinal strain). Unlike ejection fraction, FT parameters correlated significantly with age at Fontan completion, New York Heart Association (NYHA) class, and peak oxygen uptake on cardiopulmonary exercise testing. CONCLUSIONS: Assessment of myocardial function using CMR cine-based feature tracking is feasible in Fontan patients. Unlike echocardiographic techniques, FT is independent of inadequate acoustic windows and FT measurements relate to clinical parameters, suggesting that this approach could have clinical relevance in future.

Predictors of appropriate ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy: long term experience of a tertiary care center.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC. METHODS: A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation. RESULTS: Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy. CONCLUSION: In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy.

Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.

BACKGROUND: Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. METHODS AND RESULTS: We identified 5 mutations in cardiac myosin-binding protein C (MYBPC3) and 2 mutations in α-tropomyosin (TPM1) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. ß-myosin heavy chain (MYH7) was the most prevalent disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. CONCLUSIONS: Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.