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Purpose: It remains challenging to identify patients at risk of anthracycline-induced cardiotoxicity. To better understand the different risk-stratifying approaches, we evaluated (123)I-metaiodobenzylguanidine ((123)I-mIBG) scintigraphy and its interrelationship with conventional echocardiography, 2D strain imaging and several biomarkers. Methods: We performed (123)I-mIBG scintigraphy, conventional and strain echocardiography and biomarker (NT-proBNP, TNF-α, galectin-3, IL-6, troponin I, ST-2 and sFlt-1) assessment in 59 breast cancer survivors 1 year after anthracycline treatment. Interobserver and intermethod variability was calculated on planar and SPECT (123)I-mIBG scintigraphy, using the heart/mediastinum (H/M) ratio and washout (WO). Pearson's r and multivariate analyses were performed to identify correlations and independent predictors of (123)I-mIBG scintigraphy results. Results: Delayed planar anterior whole-heart ROI (WH) H/M ratios and WO were the most robust (123)I-mIBG parameters. Significant correlations were observed between (123)I-mIBG parameters and several conventional echo parameters, global longitudinal and radial strain (GLS and GRS) and galectin-3. The highest Pearson's r was observed between delayed H/M ratio and GRS (Pearson's r 0.36, p = 0.01). Multivariate analysis showed that GRS was the only independent predictor of the delayed WH H/M ratio (p = 0.023). Conclusion: The delayed planar H/M ratio is the most robust (123)I-mIBG parameter. It correlates with several conventional echocardiographic parameters, GLS, GRS and galectin-3. Of these, only GRS predicts the H/M ratio. [ABSTRACT FROM AUTHOR]

Background Cardiac biomarkers can play an important role in the early detection of subclinical heart failure. Our aims are to 1) obtain values of high sensitive cardiac troponin T (hs-cTnT) in long-term survivors of childhood cancer and 2) investigate the potential role of hs-cTnT in the detection of subclinical late-onset cardiotoxicity. Methods Hs-cTnT and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) were measured in 64 survivors. Electrocardiography and echocardiography were performed to evaluate cardiac function. Results Mean follow-up period was 8.3 years (range of 4.5 to 34.1). All survivors were clinically asymptomatic and had no history of clinical heart failure during or immediately after anthracycline treatment. Electrocardiography (available in 59 of 64 survivors) showed no signs of myocardial injury related to ischemia or abnormal QTc. Echocardiography was performed in all survivors. Mean left ventricular shortening fraction (SF) was 34% (range of 28 to 43%); mean ejection fraction (EF) was 61% (range of 48 to 74%). Seven survivors had a mildly decreased EF between 48% and 55%. Normal hs-cTnT levels were found in all 64 survivors (range of 3 to 13 ng/L) and did not differ among different anthracycline dosage groups: ≤ 120, 120–300 and ≥ 300 mg/m 2 . Yet, 5/64 survivors had elevated NT-pro-BNP levels (range of 7 to 25 pg/ml) with normal SF and ECG findings and only one mildly abnormal EF of 51%. Conclusions Hs-cTnT concentrations are normal in long-term survivors of childhood cancer, even in the subpopulations with elevated NT-pro-BNP and/or a mildly decreased EF, indicating that it is not a sensitive marker for late onset subclinical anthracycline induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Ultrasound imaging can be used to estimate the morphology as well as the motion and deformation of tissues. If the interrogated tissue is actively deforming, this deformation is directly related to its function and quantification of this deformation is normally referred as 'strain imaging'. Tissue can also be deformed by applying an internal or external force and the resulting, induced deformation is a function of the mechanical tissue characteristics. In combination with the load applied, these strain maps can be used to estimate or reconstruct the mechanical properties of tissue. This technique was named 'elastography' by Ophir et al. in 1991. Elastography can be used for atherosclerotic plaque characterisation, while the contractility of the heart or skeletal muscles can be assessed with strain imaging. Rather than using the conventional video format (DICOM) image information, radio frequency (RF)-based ultrasound methods enable estimation of the deformation at higher resolution and with higher precision than commercial methods using Doppler (tissue Doppler imaging) or video image data (2D speckle tracking methods). However, the improvement in accuracy is mainly achieved when measuring strain along the ultrasound beam direction, so it has to be considered a 1D technique. Recently, this method has been extended to multiple directions and precision further improved by using spatial compounding of data acquired at multiple beam steered angles. Using similar techniques, the blood velocity and flow can be determined. RF-based techniques are also beneficial for automated segmentation of the ventricular cavities. In this paper, new developments in different techniques of quantifying cardiac function by strain imaging, automated segmentation, and methods of performing blood flow imaging are reviewed and their application in paediatric cardiology is discussed. [ABSTRACT FROM AUTHOR]

To evaluate the role of 2D myocardial strain (rate) imaging in the detection of early subclinical cardiotoxicity in breast cancer survivors treated with an anthracycline-based chemotherapeutic regimen. 57 adult breast cancer survivors were analyzed 1 year after therapy. All patients underwent biomarker analysis and 2D echocardiography consisting of conventional echocardiographic and strain (rate) parameters. Conventional echocardiographic values were normal. Global longitudinal strain was normal, but 18 % of patients showed a >2 SD decrease when individually compared to reference values. This subgroup showed a decrease in end-systolic and end-diastolic volumes and an increase in left ventricular mass. Radial and circumferential strain rates were significantly decreased in the whole study group. 2D myocardial strain (rate) imaging showed abnormalities in breast cancer survivors, while conventional echocardiographic values remained normal, rendering 2D myocardial strain (rate) imaging an interesting tool for the early detection of anthracycline-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by 99mTc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as 99mTc multigated radionuclide angiography and 99mTc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise 1231-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; 111In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; 99mTc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and 111In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis. [ABSTRACT FROM AUTHOR]

OBJECTIVES The absence of a pulmonary valve (PV) after tetralogy of Fallot (TOF) repair has been shown to impact postoperative right ventricular (RV) function. The purposes of this study were to (i) compare early outcomes after PV-sparing vs transannular patching (TAP) with monocusp valve reconstruction or TAP alone and (b) assess the mid-term results after polytetrafluoroethylene (PTFE) membrane monocusp reconstruction. METHODS From 2003 to 2009, 163 patients underwent TOF repair. Sixty-nine patients (42.3%) underwent a PV-sparing procedure (Group A), 74 (45.4%) underwent PTFE membrane monocusp valve reconstruction (Group B) and 20 (12.3%) underwent TAP only (Group C). Early outcomes were evaluated by the right-to-left ventricular pressure ratio, RV outflow tract gradient, tricuspid and PV function, intensive care unit (ICU) parameters and need for reintervention. Group B patients were also evaluated at intermediate term for clinical and echocardiographic parameters, including tricuspid and monocusp valve function and mobility. RESULTS The median age, weight and PV Z-value of Group B patients were significantly lower; 20.5 months, 9.3 kg and −4, respectively. Postoperatively, the right-to-left ventricular pressure ratio was <0.5 in all groups. Mechanical ventilation time, fluid drainage duration and total ICU stay showed no significant difference between Groups A and B, while Group C was significantly longer (P < 0.01). There were five (3%) early deaths: three from Group A and two from Group B. The incidences of moderate or severe pulmonary insufficiency (PI) on discharge were 8.2% in Group A, 9% in Group B and 50% in Group C (P < 0.001). Among Group B patients, 85% of the evaluated patients had less than moderate PI in the intermediate-term follow-up, QRS duration <140 ms in 83.3% and right-to-left ventricular diameter ratio of 0.6 ± 0.2. Two (2.6%) patients underwent reoperation for monocusp replacement. There were two (2.7%) mid-term deaths. CONCLUSIONS The use of a PTFE membrane monocusp valve and a valve-sparing strategy prevents immediate PI and improves short-term clinical outcomes. PTFE membrane monocusp appears advantageous in preventing severe intermediate-term PI and facilitates the preservation of RV function. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation are a growing group of inborn errors of protein glycosylation. Cardiac involvement is frequently observed in the most common form, PMM2-CDG, especially hypertrophic cardiomyopathy. Dilated cardiomyopathy, however, has been only observed in a few CDG subtypes, usually with a lethal outcome. We report on cardiac pathology in nine patients from three unrelated Israeli families, diagnosed with dolichol kinase deficiency, due to novel, homozygous DK1 gene mutations. The cardiac symptoms varied from discrete, mild dilation to overt heart failure with death. Two children died unexpectedly with acute symptoms of heart failure before the diagnosis of DK1-CDG and heart transplantation could take place. Three other affected children with mild dilated cardiomyopathy at the time of the diagnosis deteriorated rapidly, two of them within days after an acute infection. They all went through successful heart transplantation; one died unexpectedly and 2 others are currently (after 1-5 years) clinically stable. The other 4 children diagnosed with mild dilated cardiomyopathy are doing well on supportive heart failure therapy. In most cases, the cardiac findings dominated the clinical picture, without central nervous system or multisystem involvement, which is unique in CDG syndrome. We suggest to test for DK1-CDG in patients with dilated cardiomyopathy. Patients with discrete cardiomyopathy may remain stable on supportive treatment while others deteriorate rapidly. Our paper is the first comprehensive study on the phenotype of DK1-CDG and the first successful organ transplantation in CDG syndrome. [ABSTRACT FROM AUTHOR]

Chemotherapy and particularly anthracycline exposure are associated with acute and chronic cardiotoxicity. Few data exist on the effect of cardiac function after in utero exposure to maternal chemotherapy. Our recently published multicenter prospective study showed no significant changes in systolic function using conventional echocardiographic parameters. The purpose of this study was to further investigate whether early functional changes can be detected using tissue Doppler imaging (TDI) and two-dimensional (2D) speckle tracking echocardiography (STE). Sixty-two children (median/range age 1.7 (1-9.8) years) exposed to chemotherapy during fetal life were enrolled and compared to 62 age- and gender-matched controls. TDI velocities were measured at the basal interventricular septum (IVS) and right and left ventricular (LV) free walls. LV global longitudinal and circumferential systolic strains were derived using 2D STE. We found small but significant differences between the groups (patients versus controls) in LV fractional shortening [35 (29-46)% versus 39 (28-53)%, p < 0.001], LV ejection fraction [66 (57-79)% versus 70 (57-83)%, p < 0.001], LV posterior wall thickness z score [−0.15 (−2.32-1.81) versus −0.10 (−1.9-2.0), p < 0.001], and IVS thickness z score [−1.06 (−2.6-1.3) versus −0.5 (−2.1-1.7), p < 0.001]. No significant differences in TDI velocities or LV global strains were observed. Within the patient group, the cardiac functional parameters did not correlate to the number of cycles of anthracycline or the cumulative anthracycline dose. Children exposed to fetal chemotherapy have a lower normal fractional shortening and mildly lower left ventricular wall thickness. Tissue Doppler and strain measurements are within normal range and not statistically different from normal controls. The long-term implications of these findings will be further studied in this prospective cohort study. [ABSTRACT FROM AUTHOR]

Objective: This study assessed clinical condition at midterm follow-up after total cavopulmonary connection for a functionally univentricular heart performed on children younger than 5 years. Methods: Thirty-four Fontan patients (median age 10.4 years, range 6.8–20.7 years, 22 boys, median follow-up 7.8 years, 5.0–17.8 years) underwent electrocardiography, Holter monitoring, bicycle exercise testing, cardiac magnetic resonance imaging, and N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) analysis. Results: Twenty-three patients (68%) were in sinus rhythm. Holter monitoring demonstrated normal mean heart rate, low maximal heart rate, and no clinically significant arrhythmias or sinus node dysfunction. With maximal bicycle ergometry (n = 19), maximum workload (60% of normal), maximum heart rate (90% of normal), and maximal oxygen uptake (69% of normal) were all significantly lower in the Fontan group than in a control group (P < .001). Variables of submaximal exercise indicated less efficient oxygen uptake during exercise in all Fontan patients. Ejection fraction was lower than in control subjects (59% ± 13% vs 69% ± 5%, P < .001). Mean end-diastolic and end-systolic volumes and ventricular mass were higher than in control subjects (P < .001). Mean NT-pro-BNP levels were increased relative to reference values, but only 8 patients had levels above the upper reference limit. Conclusion: At midterm follow-up, Fontan patients were in acceptable clinical condition, with preserved global ventricular function, moderately decreased exercise capacity, and NT-pro-BNP levels within reference range. Systemic ventricular mass was elevated, however, suggesting contractility–afterload mismatch. Long-term consequences for ventricular function merit further investigation. [Copyright &y& Elsevier]

Background: Anthracycline (ANT) is the most recognized therapy known to cause cardiotoxicity, mainly left ventricle (LV) dysfunction. Global Longitudinal Strain (GLS) is the optimal tool for assessment of subclinical LV dysfunction. Right ventricle (RV) function has been recognized as an independent factor for cardiac outcomes; however, data evaluating RV GLS is limited. We aimed to evaluate the change in RV GLS following ANT therapy. Methods: The study cohort is part of the Israel Cardio-Oncology Registry (ICOR). All patients performed echocardiography before (T1) and at the end (T3) of ANT therapy. A significant reduction was defined as a relative reduction of ≥10% in RV GLS values. Results: The study included 40 female patients with breast cancer treated with ANT. During follow-up, both RV GLS and free wall longitudinal strain systolic peak (RV FWLS PK) decreased significantly (p < 0.001 and p = 0.002). Altogether, 30 (75%) and 23 (58%) patients showed RV GLS and RV FWLS PK ≥ 10% relative reduction. At T3, LV ejection fraction and LV GLS were within normal range. Conclusions: RV GLS and RV FWLS PK reduction following ANT exposure is extremely frequent, comparing to LV GLS reduction. [ABSTRACT FROM AUTHOR]

Background. Isolated congenital atrioventricular block (CAVB) diagnosed in utero is associated with a high morbidity and mortality. Prognosis is especially poor when heart rate drops below 55 beats per minute (bpm) and when fetal hydrops develops. We describe the natural history and outcome of 24 infants with isolated CAVB diagnosed in utero, review the literature, and assess the risk factors that could predict outcome. Methods. This was a retrospective multicenter study of 24 patients with isolated CAVB diagnosed in utero. Results. CAVB was detected at a mean gestational age (GA) of 24.7 ± 5.1 weeks. Ten fetuses initially presented with complete heart block. Low heart rate or incomplete heart block was the first documentation of bradyarrhythmia in the other 14 fetuses. In 11 of them, CAVB developed during pregnancy after a median time of 3 (range 1-16) weeks. Fetal hydrops developed in 10 of 24 (42%) fetuses at a mean GA of 27.6 ± 5.1 weeks. Hydropic fetuses showed lower heart rates during pregnancy (47 ± 10 bpm) than non-hydropic fetuses (57 ± 10 bpm). There were three intrauterine deaths; all were hydropic and female. Nine viable females and 12 males were born at a mean GA of 37.1 ± 6.1 weeks with an average birth weight of 3097 ± 852 g. Fifteen CAVB patients required pacemaker (PM) intervention, 10 of them immediately after birth. Dilated cardiomyopathy (DCM) developed in three infants of whom two died of congestive heart failure, shortly after the diagnosis was made; one is still alive. Mortality before or after birth was 21%, and was associated with heart rates below 50 bpm and development of fetal hydrops. Poor outcome, defined as death, PM implantation, or development of DCM, occurred in 83% of cases and was associated with heart rates below 60 bpm during pregnancy. Conclusions. Isolated CAVB diagnosed in utero is associated with high morbidity and mortality. Patients who develop fetal hydrops show lower heart rates during pregnancy than patients who do not. A fetal heart rate below 50 bpm and development of fetal hydrops is associated with increased mortality. Rates below 60 bpm are associated with PM requirement and/or DCM. [ABSTRACT FROM AUTHOR]

Objective: Isolated fetal heart block (HB), a condition associated with fetal hydrops, carries a high mortality rate and may result in neurodevelopmental sequelae. To the best of our knowledge, no data exist regarding the long-term outcome of such hydropic fetuses. We reviewed our experience with this condition to determine the neurodevelopmental outcome of prenatally diagnosed cases with isolated HB complicated by hydrops fetalis. Methods: Neurodevelopmental assessment of 5 children presented prenatally with isolated HB associated with hydrops fetalis. Results: During the last 18 years, 10 cases were detected prenatally with isolated HB and hydrops fetalis. 3 of the 10 fetuses died in utero, and 2 died postnatally, due to a dilated cardiomyopathy, at the age of 9 months and 4 years, respectively. Neurodevelopmental studies done on the 5 remaining children were normal. Conclusion: Long-term neurodevelopmental assessments of 5 surviving cases presented prenatally with isolated HB and hydrops fetalis are reassuring. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations. Methods This prospective study investigated 14 dysmorphic features of TS girls and women using a checklist. Three major phenotypic patterns were recognized (severe phenotype, lymphatic phenotype and skeletal phenotype). Patient data including karyotype and cardio-aortic malformations (bicuspid aortic valve (BAV) and aortic coarctation (COA)) were collected. Associations between the prevalence of dysmorphic features, karyotype and cardio-aortic malformations were analysed using chi 2 -test and odds ratios. Results A total of 202 patients (84 girls and 118 women) were analysed prospectively. Differences in prevalence of dysmorphic features were found between girls and women. A strong association was found between monosomy 45,X and the phenotypic patterns. Furthermore, an association was found between COA and lymphatic phenotype, but no association was found between karyotype and cardio-aortic malformations. Conclusion This study uncovered a difference in dysmorphic features between girls and women. Monosomy 45,X is associated with a more severe phenotype, lymphatic phenotype and skeletal phenotype. All patients with TS should be screened for cardio-aortic malformations, because in contrast to previous reports, karyotype and cardio-aortic malformations showed no significant association. [ABSTRACT FROM AUTHOR]