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1.
  • Broberg, Olof, et al. (author)
  • Characterization of Cardiac, Vascular, and Metabolic Changes in Young Childhood Cancer Survivors
  • 2021
  • In: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 9
  • Journal article (peer-reviewed)abstract
    • Background: Childhood cancer survivors (CCS) are at an increased risk for cardiovascular diseases (CVD). It was the primary aim of this study to determine different measures of cardiac, carotid, lipid, and apolipoprotein status in young adult CCS and in healthy controls. Methods: Cardiac and common carotid artery (CCA) structure and function were measured by ultrasonography. Lipids and apolipoproteins were measured in the blood. Peripheral arterial endothelial vasomotor function was assessed by measuring digital reactive hyperemia index (PAT-RHI) using the Endo-PAT 2000. Results: Fifty-three CCS (20-30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50-197 mg/m2, n = 26) and a high anthracycline dose (HAD) group (200-486 mg/m2, n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls (p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls (p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls (p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls (p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF (p < 0.001) and lower é-wave (p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction (p = 0.001). Conclusion: Young asymptomatic CCS exhibit cardiac, vascular, lipid, and apolipoprotein changes that could account for increased risk for CVD later in life. These findings emphasize the importance of cardiometabolic monitoring even in young CCS.
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2.
  • Broberg, Olof, et al. (author)
  • Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer
  • 2024
  • In: Cardiology in the Young. - 1047-9511 .- 1467-1107.
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease.METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index).RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005).CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.
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4.
  • Elkinany, Sherif, et al. (author)
  • Is Aortic Z-score an Appropriate Index of Beneficial Drug Effect in Clinical Trials in Aortic Aneurysm Disease?
  • 2021
  • In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 143
  • Journal article (peer-reviewed)abstract
    • Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to “therapeutic” effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes (“filling out” of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be attributed to drug benefit. (1) We first compared body mass index (BMI) and Z-scores (Boston Children's Hospital calculator) in 361 children with “normal” single echo exams in four age ranges (0 to 1, 5 to 7, 10 to 12, 15 to 18 years). Regression analysis revealed that aging itself decreases ascending Z-score, but not root Z-score, and that increase in BMI with aging underlies the decreased Z-scores. (2) Next, we examined Z-score findings in both “normal” and Marfan children (all pharmacologically untreated) as determined on sequential echo exams over time. Of 27 children without aortic disease with sequential echos, 19 (70%) showed a natural decrease in root Z-score and 24 (89%) showed a natural decrease in ascending Z- score, over time. Of 25 untreated MFS children with sequential echos, 12 (40%) showed a natural decrease in root Z-score and 10 (33%) showed a natural decrease in ascending Z-score. Thus, Z-score is over time affected by natural factors even in the absence of any aneurysmal pathology or medical intervention. Specifically, Z-score decreases spontaneously as a natural phenomenon as children age and with fill out their BMI. Untreated Marfan patients often showed a spontaneous decrease in Z-score. In clinical drug trials in aneurysm disease, decreasing Z-score has been interpreted as a sign of beneficial drug effect. These data put such conclusions into doubt.
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5.
  • Fricke, Katrin, et al. (author)
  • Fetal cardiac magnetic resonance imaging of the descending aorta in suspected left-sided cardiac obstructions
  • 2023
  • In: Frontiers in Cardiovascular Medicine. - 2297-055X. ; 10, s. 01-10
  • Journal article (peer-reviewed)abstract
    • Background: Severe left-sided cardiac obstructions are associated with high morbidity and mortality if not detected in time. The correct prenatal diagnosis of coarctation of the aorta (CoA) is difficult. Fetal cardiac magnetic resonance imaging (CMR) may improve the prenatal diagnosis of complex congenital heart defects. Flow measurements in the ascending aorta could aid in predicting postnatal CoA, but its accurate visualization is challenging.Objectives: To compare the flow in the descending aorta (DAo) and umbilical vein (UV) in fetuses with suspected left-sided cardiac obstructions with and without the need for postnatal intervention and healthy controls by fetal phase-contrast CMR flow. A second objective was to determine if adding fetal CMR to echocardiography (echo) improves the fetal CoA diagnosis.Methods: Prospective fetal CMR phase-contrast flow in the DAo and UV and echo studies were conducted between 2017 and 2022.Results: A total of 46 fetuses with suspected left-sided cardiac obstructions [11 hypoplastic left heart syndrome (HLHS), five critical aortic stenosis (cAS), and 30 CoA] and five controls were included. Neonatal interventions for left-sided cardiac obstructions (n = 23) or comfort care (n = 1 with HLHS) were pursued in all 16 fetuses with suspected HLHS or cAS and in eight (27%) fetuses with true CoA. DAo or UV flow was not different in fetuses with and without need of intervention. However, DAo and UV flows were lower in fetuses with either retrograde isthmic systolic flow [DAo flow 253 (72) vs. 261 (97) ml/kg/min, p = 0.035; UV flow 113 (75) vs. 161 (81) ml/kg/min, p = 0.04] or with suspected CoA and restrictive atrial septum [DAo flow 200 (71) vs. 268 (94) ml/kg/min, p = 0.04; UV flow 89 vs. 159 (76) ml/kg/min, p = 0.04] as well as in those without these changes. Adding fetal CMR to fetal echo predictors for postnatal CoA did not improve the diagnosis of CoA.Conclusion: Fetal CMR-derived DAo and UV flow measurements do not improve the prenatal diagnosis of left-sided cardiac obstructions, but they could be important in identifying fetuses with a more severe decrease in blood flow across the left side of the heart. The physiological explanation may be a markedly decreased left ventricular cardiac output with subsequent retrograde systolic isthmic flow and decreased total DAo flow.
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6.
  • Fricke, Katrin, et al. (author)
  • Impact of Left Ventricular Morphology on Adverse Outcomes Following Stage 1 Palliation for Hypoplastic Left Heart Syndrome: 20 Years of National Data From Sweden
  • 2022
  • In: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 11:7
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Hypoplastic left heart syndrome is associated with significant morbidity and mortality. We aimed to assess the influence of left ventricular morphology and choice of shunt on adverse outcome in patients with hypoplastic left heart syndrome and stage 1 palliation. METHODS AND RESULTS: This was a retrospective analysis of patients with hypoplastic left heart syndrome with stage 1 palliation between 1999 and 2018 in Sweden. Patients (n=167) were grouped based on the anatomic subtypes aortic-mitral atresia, aortic atresia-mitral stenosis (AA-MS), and aortic-mitral stenosis. The left ventricular phenotypes including globular left ventricle (Glob-LV), miniaturized and slit-like left ventricle (LV), and the incidence of major adverse events (MAEs) including mortality were assessed. The overall mortality and MAEs were 31% and 41%, respectively. AA-MS (35%) was associated with both mortality (all other subtypes versus AA-MS: interstage-I: hazard ratio [HR], 2.7; P=0.006; overall: HR, 2.2; P=0.005) and MAEs (HR, 2.4; P=0.0009). Glob-LV (57%), noticed in all patients with AA-MS, 61% of patients with aortic stenosis-mitral stenosis, and 19% of patients with aortic atresia-mitral atresia, was associated with both mortality (all other left ventricular phenotypes versus Glob-LV: interstage-I: HR, 4.5; P=0.004; overall: HR, 3.4; P=0.0007) and MAEs (HR, 2.7; P=0.0007). There was no difference in mortality and MAEs between patients with AA-MS and without AA-MS with Glob-LV (P>0.15). Patients with AA-MS (35%) or Glob-LV (38%) palliated with a Blalock-Taussig shunt had higher overall mortality compared with those palliated with Sano shunts, irrespective of the stage 1 palliation year (AA-MS: HR, 2.6; P=0.04; Glob-LV: HR, 2.1; P=0.03). CONCLUSIONS: Glob-LV and AA-MS are independent morphological risk factors for adverse short-and long-term outcome, especially if a Blalock-Taussig shunt is used as part of stage 1 palliation. These findings are important for the clinical management of patients with hypoplastic left heart syndrome.
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7.
  • Hidestrand, Pip, et al. (author)
  • Impact of Underweight, Overweight, and Obesity on Health-Related Quality of Life in Children with Tetralogy of Fallot Variants
  • In: Pediatric Cardiology. - 0172-0643.
  • Journal article (peer-reviewed)abstract
    • Traditional cardiovascular risk factors put patients with congenital heart disease (CHD) at increased risk for cardiovascular morbidity and mortality. The aim of this study was to evaluate whether body mass index (BMI) is associated with health-related quality of life (HRQoL) in patients with variants of Tetralogy of Fallot (TOF). Patients and parents of children with variants of TOF–CHD were asked to fill out the PedsQL 4.0 questionnaire and provide weight and length. Patients were categorized into low, normal, and high BMI percentiles. Other demographic data were obtained from the Swedish national registry for congenital heart disease (SWEDCON). Statistical analyses included non-parametric Mann–Whitney U test, Fisher exact, and Chi-square tests. Eighty-five patients were included. Twelve were overweight or obese, 57 had a normal BMI, and 16 were underweight. There was a significant difference in age and gender between the groups. Comparing overweight/obese children to those with normal BMI, physical and social functioning were impaired, while emotional and school function were comparable between the groups. This applied to both child and parental assessment. When comparing underweight to normal weight children, school functioning assessed by the parent was the only domain significantly different from patients with a normal BMI. Children with variants of TOF and overweight/obesity have lower HRQoL, particularly in physical and social functioning, while underweight children may have impaired school functioning. We suggest that preventive measures aimed at maintaining a normal weight should be taken early in life to reduce long-term cardiovascular risk in the CHD population.
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8.
  • Hoffmann, Julia K., et al. (author)
  • Who Still Gets Ligated? Reasons for Persistence of Surgical Ligation of the Patent Ductus Arteriosus Following Availability of Transcatheter Device Occlusion for Premature Neonates
  • 2024
  • In: Journal of cardiovascular development and disease. - 2308-3425. ; 11:5
  • Journal article (peer-reviewed)abstract
    • (1) Background: To identify reasons for the persistence of surgical ligation of the patent ductus arteriosus (PDA) in premature infants after the 2019 Food and Drug Administration (FDA) approval of transcatheter device closure; (2) Methods: We performed a 10-year (2014–2023) single-institution retrospective study of premature infants (<37 weeks) and compared clinical characteristics and neonatal morbidities between neonates that underwent surgical ligation before (epoch 1) and after (epoch 2) FDA approval of transcatheter closure; (3) Results: We identified 120 premature infants that underwent surgical ligation (n = 94 before, n = 26 after FDA approval). Unfavorable PDA morphology, active infection, and recent abdominal pathology were the most common reasons for surgical ligation over device occlusion in epoch 2. There were no differences in demographics, age at closure, or outcomes between infants who received surgical ligation in the two epochs; (4) Conclusions: Despite increasing trends for transcatheter PDA closure in premature infants, surgical ligation persists due to unfavorable ductal morphology, active infection, or abdominal pathology.
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9.
  • Jeremiasen, Ida, et al. (author)
  • Vasodilator therapy for pulmonary hypertension in children : a national study of patient characteristics and current treatment strategies
  • 2021
  • In: Pulmonary Circulation. - : John Wiley & Sons. - 2045-8932 .- 2045-8940. ; 11:4
  • Journal article (peer-reviewed)abstract
    • Pulmonary vasodilator therapy is still often an off-label treatment for pulmonary hypertension in children. The aim of this nationwide register-based study was to assess patient characteristics and strategies for pulmonary vasodilator therapy in young Swedish children. Prescription information for all children below seven years of age at treatment initiation, between 2007 and 2017, was retrieved from the National Prescribed Drug Register, and medical information was obtained by linkage to other registers. All patients were categorized according to the WHO classification of pulmonary hypertension. In total, 233 patients had been prescribed pulmonary vasodilators. The treatment was initiated before one year of age in 61% (N = 143). Sildenafil was most common (N = 224 patients), followed by bosentan (N = 29), iloprost (N = 14), macitentan (N = 4), treprostinil (N = 2) and riociguat (N = 2). Over the study period, the prescription rate for sildenafil tripled. Monotherapy was most common, 87% (N = 203), while 13% (N = 20) had combination therapy. Bronchopulmonary dysplasia (N = 82, 35%) and/or congenital heart defects (N = 156, 67%) were the most common associated conditions. Eight percent (N = 18) of the patients had Down syndrome. Cardiac catheterization had been performed in 39% (N = 91). Overall mortality was 13% (N = 30) during the study period. This study provides an unbiased overview of national outpatient use of pulmonary vasodilator therapy in young children. Few cases of idiopathic pulmonary arterial hypertension were found, but a large proportion of pulmonary hypertension associated with congenital heart defects or bronchopulmonary dysplasia. Despite treatment, mortality was high, and additional pediatric studies are needed for a better understanding of underlying pathologies and evidence of treatment effects.
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10.
  • Weismann, Constance G., et al. (author)
  • Comprehensive Characterization of Arterial and Cardiac Function in Marfan Syndrome—Can Biomarkers Help Improve Outcome?
  • 2022
  • In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 13
  • Journal article (peer-reviewed)abstract
    • Background: Marfan Syndrome (MFS) has been associated with increased aortic stiffness and left ventricular dysfunction. The latter may be due to the underlying genotype and/or secondary to aortic stiffening (vascular-ventricular interaction). The aim of this study was to characterize arterial and cardiac function in MFS using a multimodal approach. Methods: Prospective observational study of MFS patients and healthy controls. Methods included echocardiography, ascending aortic distensibility, common carotid intima media thickness [cIMT], parameters of wave reflection, carotid-femoral pulse wave velocity [cfPWV]), reactive hyperemia index [RHI], and biomarker analysis (Olink, CVII panel). Results: We included 20 patients with MFS and 67 controls. Ascending aortic distensibility, cIMT and RHI were decreased, while all parameters of arterial wave reflection, stiffness and BNP levels were increased in the MFS group. Both systolic and diastolic function were impaired relative to controls. Within the MFS group, no significant correlation between arterial and cardiac function was identified. However, cfPWV correlated significantly with indexed left ventricular mass and volume in MFS. Bran natriuretic peptide (BNP) was the only biomarker significantly elevated in MFS following correction for age and sex. Conclusions: MFS patients have generally increased aortic stiffness, endothelial dysfunction and BNP levels while cIMT is decreased, supporting that the mechanism of general stiffening is different from acquired vascular disease. CfPWV is associated with cardiac size, blood pressure and BNP in MFS patients. These may be early markers of disease progression that are suitable for monitoring pharmacological treatment effects in MFS patients.
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