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2.
PLoS One ; 15(11): e0241476, 2020.
Article in English | MEDLINE | ID: mdl-33175850

ABSTRACT

INTRODUCTION: The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure. METHODS: Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent's global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection. RESULTS: MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1α signaling was downregulated while p53 signaling was predicted to be upregulated. CONCLUSION: Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.


Subject(s)
Circulating MicroRNA/blood , Gene Expression Regulation , Genome, Human , Heart Ventricles/physiopathology , Systole , Tetralogy of Fallot/genetics , Tetralogy of Fallot/physiopathology , Ventricular Dysfunction, Right/genetics , Adult , Circulating MicroRNA/genetics , Cluster Analysis , Down-Regulation/genetics , Echocardiography , Female , Heart Ventricles/diagnostic imaging , Heart Ventricles/pathology , Humans , Male , Middle Aged , Principal Component Analysis , Signal Transduction/genetics , Tetralogy of Fallot/blood , Tetralogy of Fallot/diagnostic imaging , Ventricular Dysfunction, Right/diagnostic imaging , Ventricular Dysfunction, Right/physiopathology
3.
Dis Markers ; 2020: 9356738, 2020.
Article in English | MEDLINE | ID: mdl-32774516

ABSTRACT

BACKGROUND: Pediatric patients show an impressive capacity of cardiac regeneration. In contrast, severely deteriorated adult hearts do usually not recover. Since cardiac remodeling-involving the expression of fetal genes-is regarded as an adaptation to stress, we compared hearts of adult patients suffering from dilated cardiomyopathy (DCM) with remodeling of cultured neonatal (NRC) as well as adult (ARC) rat cardiomyocytes and the developing postnatal myocardium. METHODS: NRC and ARC were stimulated with serum and cardiac morphogens derived from DCM hearts. Protein synthesis (PS) as well as protein accumulation (PA) was measured, and cell survival was determined under ischemic conditions. Fetal markers were investigated by Western blot. Biomarkers of remodeling were analyzed in controls, DCM, and 2- to 6-month-old children with tetralogy of Fallot as well as in neonatal and adult rats by immunofluorescence. RESULTS: In NRC, serum and morphogens strongly stimulated PS and PA and the reestablishment of cell-cell contacts (CCC). In ARC, both stimulants increased PS and CCC, but PA was only elevated after serum stimulation. In contrast to serum, morphogen treatment resulted in the expression of fetal genes in ARC as determined by nonmuscle α-actinin-1 and α-actinin-4 expression (NM-actinins) and was associated with increased survival under ischemia. NM-actinins were present in cardiomyocytes of DCM in a cross-striated pattern reminiscent of sarcomeres as well as in extensions of the area of the intercalated disc (ID). NM-actinins are expressed in NRC and in the developing heart. Radixin staining revealed remodeling of the area of the ID in DCM almost identical to stimulated cultured ARC. CONCLUSIONS: Remodeling was similar in ARC and in cardiomyocytes of DCM suggesting evolutionary conserved mechanisms of regeneration. Despite activation of fetal genes, the atrophy of ARC indicates differences in their regenerative capacity from NRC. Cardiac-derived factors induced NM-actinin expression and increased survival of ischemic ARC while circulating molecules were less effective. Identification of these cardiac-derived factors and determination of their individual capacity to heal or damage are of particular importance for a biomarker-guided therapy in adult patients.


Subject(s)
Actinin/metabolism , Cardiomyopathy, Dilated/metabolism , Cytoskeletal Proteins/metabolism , Membrane Proteins/metabolism , Myocytes, Cardiac/cytology , Tetralogy of Fallot/metabolism , Aged , Animals , Animals, Newborn , Cardiomyopathy, Dilated/blood , Cell Survival , Cells, Cultured , Female , Humans , Infant , Male , Middle Aged , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Tetralogy of Fallot/blood
4.
BMC Nephrol ; 21(1): 277, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32669094

ABSTRACT

BACKGROUND: Tetralogy of Fallot is the most common cyanotic congenital heart disease. Patients with the condition have a high risk of developing chronic kidney disease. Treatment of kidney disease in patients with complex hemodynamics presents unique challenges. However, there are very few reports on the treatment of end-stage renal failure in patients with tetralogy of Fallot. CASE PRESENTATION: We present a rare case of peritoneal dialysis in a 47-year-old man with tetralogy of Fallot who had not undergone intracardiac repair. Peritoneal dialysis successfully removed fluids and solutes without adversely affecting the patient's hemodynamics. Our patient was managed with peritoneal dialysis for 5 years before he succumbed to sepsis secondary to digestive tract perforation. CONCLUSIONS: In this paper, we discuss the importance of monitoring acid-base balance, changes in cyanosis, and hyperviscosity syndrome during peritoneal dialysis in patients with tetralogy of Fallot. Lower leg edema and B-type natriuretic peptide level were useful monitoring parameters in this case. This case illustrates that with attention to the patient's unique requirements, peritoneal dialysis can provide successful renal replacement therapy without compromising hemodynamics in patients with tetralogy of Fallot.


Subject(s)
Hemodynamics , Kidney Failure, Chronic/therapy , Peritoneal Dialysis/methods , Tetralogy of Fallot/physiopathology , Blalock-Taussig Procedure , Cyanosis/physiopathology , Edema , Headache/physiopathology , Hemoglobins/metabolism , Humans , Kidney Failure, Chronic/etiology , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Oxygen Inhalation Therapy , Phlebotomy , Polycythemia/blood , Polycythemia/etiology , Polycythemia/therapy , Tetralogy of Fallot/blood , Tetralogy of Fallot/complications , Tetralogy of Fallot/therapy
5.
Cardiol Young ; 29(4): 499-504, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30932800

ABSTRACT

Oxidative stress may contribute to the pathogenesis of congenital heart defects, but the role of dynamic thiol/disulphide homeostasis has not been evaluated. The objective of this study was to assess whether there are changes in thiol/disulphide homeostasis and nitric oxide levels in children with tetralogy of Fallot (TOF) and ventricular septal defect (VSD). A total of 47 children with congenital heart defects (24 TOF and 23 VSD) and 47 healthy age- and sex-matched controls were included in this study. Serum total thiol and native thiol levels were measured using a novel automatic spectrophotometric method. The amount of dynamic disulphide bonds and related ratios were calculated from these values. Serum nitric oxide levels were detected using a chemiluminescence assay. We found that the average native thiol, total thiol, and disulphide levels were decreased in patients with VSD when compared with healthy individuals (p < 0.001, p < 0.001, and p < 0.01, respectively). While native thiol levels were decreased (p < 0.01), disulphide levels were elevated in the TOF group (p < 0.05). We observed marked augmentation of disulphide/native thiol (p < 0.001) and disulphide/total thiol ratios (p < 0.01) in the TOF group. However, there was a significant decrease in native thiol/total thiol ratio in patients with TOF. No significant changes in these ratios were noted in the VSD group. We detected significant elevations in serum nitric oxide levels in children with TOF and VSD (p < 0.001 for all). These results are the first to demonstrate that thiol/disulphide homeostasis and nitric oxide are associated with TOF and VSD in children.


Subject(s)
Disulfides/blood , Heart Septal Defects, Ventricular/blood , Oxidative Stress , Sulfhydryl Compounds/blood , Tetralogy of Fallot/blood , Biomarkers/blood , Case-Control Studies , Child , Child, Preschool , Female , Homeostasis , Humans , Infant , Male , Nitric Oxide/blood , Turkey
6.
J Card Surg ; 34(6): 463-467, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31025765

ABSTRACT

BACKGROUND: To investigate the effects of systemic-to-pulmonary shunts (SPSs) in older children with hypoplastic pulmonary arteries and the factors affecting the development of the pulmonary arteries. METHODS: Eighty-six children (older than 3 years) who received SPSs were retrospectively analyzed. The perioperative parameters, the postoperative diameter of the pulmonary artery were collected, and the factors influencing the growth of the pulmonary arteries after an initial palliative shunt operation were analyzed. RESULTS: Two patients died postoperatively (2.33%), and the pulse oxygen saturation (SpO2 ) increased from 71.70 ± 6.75% preoperatively to 85.20 ± 11.07% at discharge. During the follow-up period of 56 (10-99) months, 37 patients (43.02%) underwent subsequent procedures, and in the remaining patients, the McGoon ratio was increased from 0.96 ± 0.48 at the surgery to 1.30 ± 0.31 at the final assessment (P < 0.05). Univariate analysis indicated that age younger than 5 years old (P < 0.05), pulmonary artery forward flow (P < 0.05) and a diagnosis of tetralogy of Fallot (P < 0.05) played positive roles in the growth of the pulmonary artery after surgery, while children with a McGoon ratio less than 0.6 showed poor development of the pulmonary arteries (P < 0.05). Multivariate analysis showed that age younger than 5 years old (P < 0.05) and pulmonary artery forward flow (P < 0.05) were positive effectors on the growth of the pulmonary artery. CONCLUSIONS: Older children with cyanotic congenital heart disease benefited from a systemic-pulmonary shunt and showed increased postoperative oxygen saturation and development of the pulmonary arteries. Age younger than 5 years and pulmonary artery antegrade flow were the positive factors influencing the growth of the pulmonary arteries postoperatively.


Subject(s)
Blalock-Taussig Procedure/methods , Heart Defects, Congenital/surgery , Pulmonary Artery/growth & development , Pulmonary Artery/surgery , Adolescent , Child , Child, Preschool , Female , Heart Defects, Congenital/blood , Humans , Infant , Male , Oxygen/blood , Pulmonary Artery/abnormalities , Retrospective Studies , Tetralogy of Fallot/blood , Tetralogy of Fallot/surgery
7.
Perfusion ; 34(6): 495-502, 2019 09.
Article in English | MEDLINE | ID: mdl-30848697

ABSTRACT

BACKGROUND: Myocardial protection in Tetralogy of Fallot patients undergoing intracardiac repair is suboptimal due to hypertrophied right ventricle. Hypertrophied myocardium is more susceptible to poor myocardial preservation because of inadequate capillary density as compared to the myocytes. There is a capillary to myocyte ratio mismatch. But del Nido Cardioplegia owing to its less viscosity is able to get more evenly distributed under hypothermic cardiopulmonary bypass as opposed to blood Cardioplegia. We hypothesized that the del Nido Cardioplegia technique, would be beneficial in myocardial protection because of its composition and method of delivery, leading into better early and late clinical outcomes in patients undergoing Tetralogy of Fallot repair as compared to blood cardioplegia reconstituted using St Thomas Cardioplegia solution. The objective of the study was to identify a better technique of myocardial preservation in Tetralogy of Fallot patient. METHODS: In total, 56 Tetralogy of Fallot patients undergoing intracardiac repair under mild hypothermic cardiopulmonary bypass were randomly allocated to receive antegrade Cardioplegia with either standard blood Cardioplegia (Group I) or del Nido Cardioplegia (Group II). Preoperative as well as postoperative data including echocardiographic parameters for right ventricle functions, creatine kinase MB level, inotropic requirement, mechanical ventilation duration, intensive care unit stay and hospital mortality were evaluated. RESULTS: Inotropic score in the first 24 hours postoperatively was significantly lower in Group II compared to Group I (13.4 ± 7.2 vs. 21.2 ± 9.6, p = 0.003). Creatine kinase MB level (ng/mL) was comparable between the groups. Echocardiographic parameters for right ventricle functions were also comparable between the groups during early as well as after 3 to 6 months postoperatively. CONCLUSION: Del Nido Cardioplegia is equally efficacious in providing myocardial protection during intracardiac repair under mild hypothermic cardiopulmonary bypass in Tetralogy of Fallot patients as compared to blood Cardioplegia solution with the added benefit of reducing inotropic requirement in first 24 hours postoperative period.


Subject(s)
Cardioplegic Solutions/administration & dosage , Cardiopulmonary Bypass , Heart Arrest, Induced , Tetralogy of Fallot , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Tetralogy of Fallot/blood , Tetralogy of Fallot/physiopathology , Tetralogy of Fallot/surgery
8.
Circ J ; 83(4): 818-823, 2019 03 25.
Article in English | MEDLINE | ID: mdl-30799372

ABSTRACT

BACKGROUND: There are no reports on the effect of red blood cell distribution width (RDW) in surgical repair of tetralogy of Fallot (ToF). Methods and Results: A total of 50 patients who underwent cardiac catheterization after surgical repair of ToF were retrospectively assessed. RDW was positively correlated with the ratio of right ventricular pressure to left ventricular pressure (RVP/LVP; P<0.0001, r2=0.57). Patients with elevated RDW had a higher RVP/LVP than those with a normal RDW (P<0.0001). Also, elevated RDW was related to elevated central venous pressure (P<0.0001), decreased mixed venous oxygen saturation (P<0.0001), greater pulmonary stenosis (P=0.003) and severe pulmonary regurgitation on echocardiography (P<0.0001), a higher rate of residual ventricular septal defect leak (P=0.004) and higher reoperation rate (P=0.009). Of the 7 patients who underwent reoperation, 6 had decrease in RDW after reoperation (P=0.012). On multivariable regression analysis, RDW was the strongest indicator of higher RVP/LVP. CONCLUSIONS: For the first time, RDW has been shown to be a strong indicator for assessing the hemodynamics and risk of later reoperation after surgical repair of ToF.


Subject(s)
Erythrocyte Indices , Hemodynamics , Tetralogy of Fallot/blood , Central Venous Pressure , Female , Humans , Infant , Male , Reoperation , Retrospective Studies , Risk , Tetralogy of Fallot/surgery , Ventricular Function, Left , Ventricular Function, Right
9.
Asian Cardiovasc Thorac Ann ; 27(2): 75-79, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30580530

ABSTRACT

BACKGROUND: Cardioplegia is an integral part of myocardial protection. The superiority of blood cardioplegia in adult patients has been reported. However, this is yet to be studied in cyanotic pediatric patients. METHODS: A randomized open-label trial was conducted in 70 patients with tetralogy of Fallot. They were divided into two groups: 35 patients had crystalloid cardioplegia (controls), and 35 had blood cardioplegia. Lactate and coronary oxygen extraction in arterial blood and the coronary sinus were measured immediately after cessation of cardiopulmonary bypass, 15 and 30 min later. Postoperative mortality, major adverse cardiac events, mechanical ventilation time, inotrope administration, arrhythmias, right ventricular function, intensive care unit and hospital length of stay were observed. RESULTS: There were no significant differences in clinical outcomes or lactate levels. There was a significant difference in coronary oxygen extraction immediately and 15 min after cessation of cardiopulmonary bypass ( p = 0.038, p = 0.015). CONCLUSION: Blood cardioplegia gave a better postoperative oxygen extraction value but there were no differences in myocardial damage or clinical outcome between the two groups.


Subject(s)
Cardiac Surgical Procedures , Cardioplegic Solutions/therapeutic use , Cardiopulmonary Bypass , Heart Arrest, Induced/methods , Potassium Compounds/therapeutic use , Tetralogy of Fallot/surgery , Adolescent , Adult , Biomarkers/blood , Cardiac Surgical Procedures/adverse effects , Cardioplegic Solutions/adverse effects , Cardiopulmonary Bypass/adverse effects , Child , Child, Preschool , Cyanosis/blood , Cyanosis/etiology , Female , Heart Arrest, Induced/adverse effects , Humans , Indonesia , Infant , Infant, Newborn , Lactic Acid/blood , Male , Oxygen/blood , Postoperative Complications/etiology , Potassium Compounds/adverse effects , Risk Factors , Tetralogy of Fallot/blood , Tetralogy of Fallot/complications , Tetralogy of Fallot/diagnostic imaging , Time Factors , Treatment Outcome , Young Adult
10.
Am J Cardiol ; 122(12): 2125-2130, 2018 12 15.
Article in English | MEDLINE | ID: mdl-30293655

ABSTRACT

The aim of this study was to temporally measure N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over a period of 18 months after corrective surgery among children with tetralogy of Fallot (TOF) and to explore how commonly used pharmaceuticals (i.e., spironolactone and digoxin) might affect the normalization pattern. This retrospective study included 136 children with a median age of 7 months who underwent cardiac surgery for TOF. NT-proBNP level was measured at 1, 3, 6, 12, and 18 months after the surgery. Normalization of NT-proBNP was defined as an NT-proBNP level ≤250 pg/ml. The commonly used pharmaceuticals spironolactone and digoxin after discharge were collected. The normalization pattern, normalization time, and potential influence of the pharmaceuticals were determined. The rate of normalization was 24.2% (95% confidence interval [CI] 8.58% to 68.4%) per 100 person-days. Kaplan-Meier survival analysis showed a median normalization time of 517 (95% CI 429.6 to 604.3) days. The children whose NT-proBNP level did not normalize had a significantly higher readmission rate than those whose NT-proBNP level normalized (19.0% vs 2.8%, p = 0.018). Multivariable logistic regression models confirmed that the regular users of spironolactone, alone (odds ratio = 1.45, 95% CI 1.15 to 1.83) or in combination with digoxin (odds ratio = 1.28, 95% CI 1.03 to 1.58), had markedly faster recovery trajectories for measures of NT-proBNP than the irregular users of both. In conclusion, NT-proBNP normalization after cardiac surgery for TOF is a lengthy process, and irregular use of spironolactone could lead to failure in recovery and hospital readmission.


Subject(s)
Cardiac Surgical Procedures/methods , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Recovery of Function , Tetralogy of Fallot/blood , Biomarkers/blood , Female , Follow-Up Studies , Humans , Infant , Male , Postoperative Period , Prognosis , Protein Precursors , ROC Curve , Retrospective Studies , Tetralogy of Fallot/surgery
11.
PLoS One ; 13(9): e0203893, 2018.
Article in English | MEDLINE | ID: mdl-30212560

ABSTRACT

Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.


Subject(s)
Epigenesis, Genetic , Tetralogy of Fallot/blood , Tetralogy of Fallot/genetics , Area Under Curve , Computational Biology , CpG Islands , DNA Methylation , Genome-Wide Association Study , Humans , Infant, Newborn , ROC Curve , Signal Transduction
12.
Eur Heart J ; 39(12): 1028-1037, 2018 03 21.
Article in English | MEDLINE | ID: mdl-28329231

ABSTRACT

Aims: Remote ischaemic preconditioning (RIPC) by inducing brief ischaemia in distant tissues protects the heart against myocardial ischaemia-reperfusion injury (IRI) in children undergoing open-heart surgery, although its effectiveness in adults with comorbidities is controversial. The effectiveness and mechanism of RIPC with respect to myocardial IRI in children with tetralogy of Fallot (ToF), a severe cyanotic congenital cardiac disease, undergoing open heart surgery are unclear. We hypothesized that RIPC can confer cardioprotection in children undergoing ToF repair surgery. Methods and results: Overall, 112 ToF children undergoing radical open cardiac surgery using cardiopulmonary bypass (CPB) were randomized to either a RIPC group (n = 55) or a control group (n = 57). The RIPC protocol consisted of three cycles of 5-min lower limb occlusion and 5-min reperfusion using a cuff-inflator. Serum inflammatory cytokines and cardiac injury markers were measured before surgery and after CPB. Right ventricle outflow tract (RVOT) tissues were collected during the surgery to assess hypoxia-inducible factor (Hif)-1α and other signalling proteins. Cardiac mitochondrial injury was assessed by electron microscopy. The primary results showed that the length of stay in the intensive care unit (ICU) was longer in the control group than in the RIPC group (52.30 ± 13.43 h vs. 47.55 ± 10.34 h, respectively, P = 0.039). Patients in the control group needed longer post-operative ventilation time compared to the RIPC group (35.02 ± 6.56 h vs. 31.96 ± 6.60 h, respectively, P = 0.016). The levels of post-operative serum troponin-T at 12 and 18 h, CK-MB at 24 h, as well as the serum h-FABP levels at 6 h, after CPB were significantly lower, which was coincident with significantly higher protein expression of cardiac Hif-1α, p-Akt, p-STAT3, p-STAT5, and p-eNOS and less vacuolization of mitochondria in the RIPC group compared to the control group. Conclusion: In ToF children undergoing open heart surgery, RIPC attenuates myocardial IRI and improves the short-term prognosis.


Subject(s)
Cardiac Surgical Procedures/methods , Ischemic Preconditioning/methods , Preoperative Care/methods , Telemedicine/methods , Tetralogy of Fallot/surgery , Biomarkers/blood , Child, Preschool , Cytokines/blood , Female , Follow-Up Studies , Humans , Infant , Male , Tetralogy of Fallot/blood , Time Factors , Treatment Outcome , Troponin I/blood
13.
Adv Med Sci ; 63(1): 112-118, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29111402

ABSTRACT

PURPOSE: This retrospective cohort study aimed to identify the early postoperative kinetics of C-reactive protein (CRP) and procalcitonin (PCT) in children undergoing tetralogy of Fallot (ToF) correction. The ability of these inflammatory markers to guide rational antibiotic usage was also determined. MATERIALS AND METHODS: All consecutive children who underwent ToF correction in 2009-2016 in our referral pediatric cardiac surgery clinic in Gdansk, Poland and did not exhibit infection signs on early postoperative days (POD) were identified. All patients received 48h antibiotic prophylaxis. Antibiotic treatment was extended or empirical antibiotic therapy was introduced if the clinician considered it necessary. CRP and PCT levels were measured on POD1-4 and 1-3, respectively. RESULTS: Of the 60 eligible children, 44 underwent CRP testing only. The remaining 16 patients underwent both CRP and PCT testing. All patients had abnormally high CRP values after surgery. All patients who also underwent PCT testing also displayed elevated PCT levels. The CRP and PCT levels peaked on POD2 (median=99.8mg/L) and POD1 (median=4.08ng/mL), respectively. In the CRP-alone patients, antibiotic prophylaxis was prolonged or empirical antibiotic therapy was started in 59%; in the CRP and PCT group, this was 25% (p<0.05). CONCLUSIONS: The children had elevated CRP and PCT levels after ToF correction, with peaks observed on POD2 and POD1, respectively. Monitoring both CRP and PCT in the early postoperative period may guide antibiotic therapy, thus reducing unnecessary treatment, additional toxicity, and adverse drug interactions without increasing treatment failure. Rational antibiotic treatment may also reduce antibiotic resistance.


Subject(s)
Anti-Bacterial Agents/therapeutic use , C-Reactive Protein/metabolism , Calcitonin/blood , Tetralogy of Fallot/blood , Tetralogy of Fallot/surgery , Antibiotic Prophylaxis , Child , Demography , Female , Humans , Kinetics , Male , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Postoperative Period , Tetralogy of Fallot/drug therapy
14.
J Cell Biochem ; 119(1): 468-477, 2018 01.
Article in English | MEDLINE | ID: mdl-28598000

ABSTRACT

Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease. To identify endogenous peptides possibly involved in the progression of TOF, we performed comparative peptidomic profiling of maternal serum between normal fetuses and fetuses suffering from TOF. A total of 278 differentially expressed peptides, including 94 over-expressed peptides and 184 under-expressed peptides, originating from 227 protein precursors were identified by liquid chromatography/mass spectrometry (LC/MS) in maternal serum of fetuses with TOF compared to normal controls. Further, ingenuity pathway analysis (IPA) was used to identify putative roles for these peptides in cardiovascular development. Two peptides were derived from functional domains of proteins involved in heart development and associated with TOF; these may represent candidate bioactive peptides involved in TOF. These peptides may be related to the pathologic changes in the heart associated with TOF, and may be useful as novel biomarkers for prenatal diagnosis of TOF. J. Cell. Biochem. 119: 468-477, 2018. © 2017 Wiley Periodicals, Inc.


Subject(s)
Fetal Diseases/blood , Peptides/blood , Prenatal Diagnosis/methods , Proteomics/methods , Tetralogy of Fallot/blood , Adult , Biomarkers/blood , Female , Fetal Diseases/diagnosis , Humans , Pregnancy , Tetralogy of Fallot/diagnosis
15.
J Transl Med ; 15(1): 156, 2017 07 10.
Article in English | MEDLINE | ID: mdl-28693530

ABSTRACT

BACKGROUND: MicroRNAs (miRNAs) are a class of regulatory RNAs that regulate gene expression post-transcriptionally. Little, however, is known on the expression profile of circulating miRNAs in Tetralogy of Fallot (TOF) patients late after surgical repair. In this study, we aimed to identify the specific patterns of circulating miRNAs in blood of patients with repaired, non-syndromic TOF and to assess whether these specific miRNAs may be useful to differentiate patients with and without heart failure. METHODS: SurePrint™ 8 × 60 K Human v16 miRNA arrays were used to determine miRNA expression profiles in 15 healthy controls and 37 patients after TOF repair of whom 3 had symptomatic right heart failure. The expression levels of selected miRNAs have been validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Enrichment analyses of altered miRNA expression were predicted using bioinformatic tools. RESULTS: Compared with healthy controls, a total of 49, 58 and 77 miRNAs were found to be significantly altered in TOF patients (TOF-all), TOF patients with (TOF-HF) and without symptomatic right heart failure (TOF-noHF) (>2.0-fold change, adjusted P < 0.05), respectively. Three miRNAs namely miR-181d-5p, miR-206 and miR-625-5p were validated by RT-qPCR in all TOF groups. The area under the receiver operating characteristic curve (AUC) for miR-181d-5p, miR-206 and miR-625-5p were 0.987, 0.993 and 0.769 in TOF-all and 0.990, 0.994 and 0.749 in TOF-noHF, respectively. Moreover, expression levels of miR-625-5p, miR-1233-3p and miR-421 were lower in TOF-HF compared to TOF-noHF (P = 0.012). CONCLUSIONS: Altered expression levels of circulating miRNAs were found in TOF patients late after surgical repair and are different to those seen in the right ventricular myocardium of infants with TOF. Expression levels of miR-421, miR-1233-3p and miR-625-5p are lower in TOF patients with symptomatic right heart failure and thus may indicate disease progression in these patients.


Subject(s)
Circulating MicroRNA/genetics , Heart Failure/blood , Heart Failure/genetics , Tetralogy of Fallot/blood , Tetralogy of Fallot/genetics , Adult , Circulating MicroRNA/metabolism , Female , Gene Expression Profiling , Heart Failure/complications , Humans , Male , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Tetralogy of Fallot/complications
16.
J Int Med Res ; 45(2): 493-503, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28415932

ABSTRACT

Objective To investigate the influence of surgical correction on biomarkers of endothelial dysfunction in children with congenital heart disease and to evaluate anthropometric data. Methods Children with pulmonary hypertension (PH) or Tetralogy of Fallot (TOF) who were scheduled for corrective surgery were enrolled in this prospective study. Age-matched healthy children were included as controls. Demographic, haemodynamic and cardiac ultrasonography data were collected. Blood samples were taken pre-surgery, 24-48 hours post-surgery and again 3-6 months later. Several biomarkers (protein C, soluble platelet selectin [CD62P], soluble endothelium selectin [CD62E], soluble leukocyte selectin [CD62L], plasma von Willebrand Factor [vWF] atrial natriuretic peptide [ANP], brain natriuretic peptide[(BNP] and insulin-like growth factor-1 [IGF-1]) were measured. Results Sixty-three children (32 with PH, 15 with TOF, and 16 controls) were enrolled. No significant differences between the PH and TOF groups were observed in the expression of biomarkers pre- and post-surgery. IGF-1 levels were closely related to anthropometric data, particularly those children with PH. Expression of IGF-1 and weight/height normalized after corrective surgery. Conclusions No significant endothelial dysfunction was observed in children with PH or TOF before or after corrective surgery. Significant retardation of growth, particularly weight, was found before surgery and may be related to IGF-1 suppression.


Subject(s)
Hypertension, Pulmonary/blood , Insulin-Like Growth Factor I/metabolism , Tetralogy of Fallot/blood , Anthropometry , Atrial Natriuretic Factor/blood , Biomarkers/blood , Case-Control Studies , E-Selectin/blood , Female , Humans , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/pathology , Infant , Infant, Newborn , L-Selectin/blood , Male , Natriuretic Peptide, Brain/blood , P-Selectin/blood , Prospective Studies , Protein C/metabolism , Tetralogy of Fallot/diagnostic imaging , Tetralogy of Fallot/pathology , Tetralogy of Fallot/surgery , Ultrasonography , von Willebrand Factor/metabolism
17.
Perfusion ; 32(5): 394-402, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28152655

ABSTRACT

BACKGROUND: Long intervals of del Nido (DN) solution administration, 90 minutes, may result in rewarming of the myocardial tissue and elevate metabolic demand and hypoxia. This will potentially increase inflammatory response due to ischemia-reperfusion injury. We conducted this study to compare the inflammatory response between patients receiving DN and multi-dose St Thomas' cardioplegia solution (MST) in cardiopulmonary bypass (CPB) surgery for the correction of tetralogy of Fallot (TF). METHODS: Fifty-nine pediatric patients undergoing TF total correction surgery were randomly assigned into two groups: DN and MST. The patients' demographic data, blood chemistry parameters, hemodynamics and other clinical variables were recorded. TNF-a, IL-6, IL-8, IL-10 and cTnI were measured after anesthesia induction (before skin incision), immediately after cross-clamp removal and 24 hours after admission to the intensive care unit (ICU). RESULTS: Thirty-two patients of a mean age of 28.0±16.4 months received DN and 27 patients of a mean age of 24.2±15.9 months received MST. Perioperative clinical parameters were not significantly different between the two groups. Cytokine levels for all patients were significantly increased after surgery. Inter-group comparisons of cytokine levels demonstrated no significant differences in TNF-α, IL-6 and IL-8 cytokines levels. IL-10 level showed a moderately significant increase in the MST group compared to the DN group after surgery (2.94±0.9 vs. 2.46±0.61 log10 pg/mL, respectively; p=0.039). Postoperative lactate level was significantly different between two groups (2.475±1.29 vs 1.63±0.82 mg/dL in DN and MST groups, respectively; p=0.007). CTnI levels increased after surgery and remained constant until 24 hours after surgery. Significant differences between the MST and DN groups, at all times, were not detected. CONCLUSIONS: The anti-inflammatory cytokine response in the MST group is significantly better than in the DN group. This may be due to shorter intervals of the MST cardioplegia solution administration, which prevents rewarming of the myocardium, increased metabolic demand and hypoxia. Decreasing the intervals of DN administration may improve its cardioprotective properties.


Subject(s)
Cardioplegic Solutions/administration & dosage , Cardiopulmonary Bypass/methods , Cytokines/blood , Tetralogy of Fallot/blood , Tetralogy of Fallot/surgery , Troponin I/blood , Child, Preschool , Female , Humans , Infant , Inflammation/blood , Male , Time Factors
19.
Anesth Analg ; 123(3): 722-30, 2016 09.
Article in English | MEDLINE | ID: mdl-27537760

ABSTRACT

BACKGROUND: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF. METHODS: Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 µg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min. CONCLUSIONS: A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.


Subject(s)
Etomidate/blood , Hypnotics and Sedatives/blood , Metabolic Clearance Rate/physiology , Tetralogy of Fallot/blood , Tetralogy of Fallot/physiopathology , Etomidate/administration & dosage , Female , Humans , Hypnotics and Sedatives/administration & dosage , Infant , Infusions, Intravenous , Male , Metabolic Clearance Rate/drug effects , Tetralogy of Fallot/drug therapy
20.
Ann Card Anaesth ; 19(2): 217-24, 2016.
Article in English | MEDLINE | ID: mdl-27052060

ABSTRACT

BACKGROUND: The identification of biomarkers for predicting morbidity and mortality, particularly in pediatric population undergoing cardiac surgery will contribute toward improving the patient outcome. There is an increasing body of literature establishing the clinical utility of hyperlactatemia and lactate clearance as prognostic indicator in adult cardiac surgical patients. However, the relationship between lactate clearance and mortality risk in the pediatric population remains to be established. OBJECTIVE: To assess the role of lactate clearance in determining the outcome in children undergoing corrective surgery for tetralogy of Fallot (TOF). METHODS AND STUDY DESIGN: A prospective, observational study. SETTING: A tertiary care center. STUDY POPULATION: Two hundred children undergoing elective surgery for TOF. STUDY METHOD: Blood lactate levels were obtained as baseline before operation (T0), postoperatively at admission to the cardiac intensive care unit after surgery (T1), and then at every 6 h for the first 24 h of Intensive Care Unit (ICU) stay (T6, T12, T18, and T24, respectively). The lactate clearance in the study is defined by the equation ([lactate initial - lactate delayed]/lactate initial) ×100%. Lactate clearance was determined at T1-T6, T1-T12, T1-T18, and T1-T24 time interval, respectively. The primary outcome measured was mortality. Secondary outcomes measured were the duration of mechanical ventilation, duration of inotropic requirement, and duration of ICU stay. RESULTS: Eleven out of the two hundred patients enrolled in the study died. Nonsurvivors had higher postoperative lactate concentration (P < 0.05) and low-blood lactate clearance rate during 24 h (P < 0.05) in comparison to the survivors. Lactate clearance was significantly higher in survivors than in nonsurvivors for the T1-T6 period (19.55 ± 14.28 vs. 5.24 ± 27.79%, P = 0.009) and remained significantly higher for each studied interval in first 24 h. Multivariate logistic regression analysis of statistically significant univariate variables showed early lactate clearance to have a significant relationship with mortality. Patients with a lactate clearance >10%, relative to patients with a lactate clearance <10%, in the early postoperative period, had improved outcome and lower mortality. CONCLUSION: Lactate clearance in the early postoperative period (6 h) is associated with decreased mortality rate. Patients with higher lactate clearance (>10%) after 6 h have improved outcome compared with those with lower lactate clearance.


Subject(s)
Cardiac Surgical Procedures/mortality , Lactic Acid/blood , Tetralogy of Fallot/mortality , Tetralogy of Fallot/surgery , Algorithms , Cardiopulmonary Bypass , Cardiotonic Agents/therapeutic use , Child, Preschool , Critical Care , Female , Humans , Male , Postoperative Period , Predictive Value of Tests , Prospective Studies , Respiration, Artificial , Tetralogy of Fallot/blood , Treatment Outcome
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