Salmonella Typhimurium Myocarditis in Two Previously Healthy Children.

Myocarditis represents an inflammation affecting the heart muscles, a condition relatively uncommon among children. Its diagnosis poses challenges due to the diverse range of its non-specific symptoms. Non-typhoidal Salmonella (NTS) species are known as rare but noteworthy contributors to myocarditis, especially among immunocompetent young patients. We present two cases of NTS myocarditis in previously healthy children, in an attempt to shed light on the epidemiology, diagnostic methods, and prognosis, aiming to offer a greater understanding of this rare condition.

Role of FGF21 and Leptin for the Diagnosis of Metabolic Health in Children with and without Obesity.

Obesity and unfavorable metabolic profiles increase the risk for cardiovascular complications in adults. Although it is important to distinguish different metabolic health states at an early stage, there are limited data on the related value of biomarkers in childhood. We aimed to identify biomarkers for the detection of different metabolic health states in children with and without obesity. The serum levels of metabolic regulators (fibroblast growth factor 21 [FGF21], leptin, adiponectin and insulin-like growth factor binding protein 1) and vascular indices (flow-mediated dilation [FMD] and carotid intima-media thickness) were assessed in 78 children. Differences between the metabolically healthy and unhealthy state within children with normal weight (MHN vs. MUN), and within children with overweight/obesity (MHO vs. MUO) were investigated; the discriminatory power of the biomarkers was studied. Both MUN and MUO groups expressed altered lipid and glucose homeostasis compared to their healthy counterparts. The metabolic unhealthy state in children with normal weight was linked to higher FGF21 levels which had good discriminatory ability (area under the curve [AUC]: 0.71, 95% CI: 0.54-0.88; p = 0.044). In overweight/obese children, leptin was increased in the metabolically unhealthy subgroup (AUC: 0.81, 95% CI: 0.68-0.95; p = 0.01). There was a decrease in FMD indicating worse endothelial function in overweight/obese children versus those with normal weight. Distinct states of metabolic health exist in both children with normal weight and overweight/obese children. FGF21 and leptin may help to identify the metabolic unhealthy state in children with normal weight and in overweight/obese children, respectively, early in life.

Serum PCSK9 levels in infants with deviant birth weight: a biomarker of the lipoprotein metabolism.

OBJECTIVE: Proprotein Convertase Subtilisin/Kexin-Type 9 (PCSK9), a modulator of low-density lipoprotein (LDL) cholesterol metabolism, has been reported to be a promising biomarker for evaluating lipoprotein metabolism; however, evidence in infants is limited. In the current study, we sought to investigate potential differences in serum PCSK9 levels between infants with deviant birth weight and controls. METHODS: We enrolled 82 infants, classified into 33 small (SGA), 32 appropriate (AGA), and 17 large for gestation (LGA) infants. Serum PCSK9 was measured on routine blood analysis within the first postnatal 48 h. RESULTS: PCSK9 was significantly higher in SGA as compared to AGA and LGA infants [322 (236-431) as compared to 263 (217-302) and 218 (194-291) ng/ml respectively, p = .011]. In comparison to term AGA infants, PCSK9 was significantly elevated in preterm AGA and SGA infants. We also found a significantly higher level of PCSK9 in term female SGA infants as compared to term male SGA infants [325 (293-377) as compared to 174 (163-216) ng/ml, p = .011]. PCSK9 was significantly correlated with gestational age (R = -0.404, p < .001), birth weight (R = -0.419, p < .001), total cholesterol (R = 0.248, p = .028) and LDL cholesterol (R = 0.370, p = .001). SGA status (OR 2.56, p = .004, 95% CI 1.83-4.28) and prematurity (OR 3.10, p = .001, 95% CI 1.39-4.82) were strongly related to serum PCSK9 levels. CONCLUSION: PCSK9 levels were significantly associated with total and LDL cholesterol. Moreover, PCSK9 levels were higher in preterm and SGA infants, suggesting that PCSK9 might be a promising biomarker for evaluating infants with increased later cardiovascular risk.HighlightsWhat's already known? Proprotein Convertase Subtilisin/Kexin-Type 9 (PCSK9) is a promising biomarker for evaluating lipoprotein metabolism; however, evidence in infants is limited. Infants that were born with a deviant birth weight have a unique lipoprotein metabolism profile.What this study adds? Serum PCSK9 levels were significantly associated with total and LDL cholesterol. PCSK9 levels were higher in preterm and small for gestation infants, suggesting that PCSK9 might be a promising biomarker for evaluating infants with increased later cardiovascular risk.

Biomarkers of cardiovascular disease risk in the neonatal population.

The consistently high prevalence of cardiovascular disease (CVD) has urged the need for punctual and effective prevention. Extended research on this specific area has demonstrated the influence of fetal and neonatal periods on the risk of developing CVD in adulthood. Thus, the role of traditional and novel biological markers to the effective screening of CVD among the neonatal population is widely investigated. The objective of the present narrative review is to examine those neonatal biomarkers that may play a role in the development of CVD, to exhibit scientific data that appertain to their association with various perinatal conditions leading to CVD predisposition, and their potential role on prediction and prevention strategies. Multiple biomarkers, traditional and novel, have been mined across the studied literature. Adiposity, insulin resistance, altered lipid profile, inflammation, and endothelial dysfunction seem among the headliners of CVD. Even though various novel molecules have been studied, their clinical utility remains controversial. Therefore, it is quite important for the scientific community to find elements with strong predictive value and practical clinical use.

Unusual Manifestations of Kawasaki Disease in the COVID Era: A Case Series and Review of the Literature.

Kawasaki disease (KD) is an acute medium-vessel vasculitis, mainly affecting infants older than six months and children under five years. It predisposes to the development of coronary artery aneurysms and constitutes the leading cause of acquired heart disease in children. Its diagnosis is based on clinical criteria, namely, fever lasting for ≥ five days together with at least four of the five principal clinical features of the disease. Occasionally, children with KD present with fever, but they fulfill only some of the five principal criteria, and this is described as incomplete KD. Furthermore, "atypical" KD is a term that is usually used for cases that appear with rather unusual clinical manifestations, which complicate clinical judgment and may delay diagnosis and treatment. In this case series, we present four cases of KD with rather unusual clinical features: a five-year-old boy with lobar pneumonia, a six-year-old girl with orange-brown chromonychia appearing on the 10th day of the disease, a 2.5-month-old infant with prolonged fever and urinary tract infection, and an 18-month-old infant with refractory KD and high suspicion of multisystem inflammatory syndrome in children (MIS-C). A literature review on the unusual manifestations of atypical KD was performed to identify clinical findings that must alert the clinician to consider this clinical entity.

Prolonged QT Interval in Athletes: Distinguishing between Pathology and Physiology.

BACKGROUND: The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered in athletes with QT prolongation. SUMMARY: According to international recommendations for electrocardiogram in athletes, further evaluation for long QT syndrome (LQTS) is indicated in male athletes with corrected QT (QTc) ≥470 ms and in female athletes with QTc ≥480 ms. Apart from QTc ≥500 ms, diagnostic challenges arise in borderline cases of QTc prolongation, where further clinical investigations are needed to be performed to clarify whether LQTS exists. Clinical diagnostic investigations, including exercise testing, are more readily available, convenient, and easily interpretable, as well as less costly than genetic testing for LQTS. The main findings on exercise testing that are suggestive of LQTS can be the paradoxical prolongation of QTc during exercise and QTc ≥480 ms at fourth min of recovery. KEY MESSAGES: Exercise testing appears to have an important role in the diagnostic evaluation of athletes with prolonged QT interval, when genetic testing is not available.

Evolution of electrocardiographic abnormalities and arrhythmias in adult patients with beta-thalassemia major during a short-term follow-up.

OBJECTIVE: Adult beta-thalassemia major (TM) patients exhibit electrocardiographic abnormalities and cardiac autonomic dysfunction. We aimed to investigate the evolution of electrocardiographic abnormalities and arrhythmias in TM patients during a 12-month follow-up period. METHODS: Forty-seven adult TM patients (median age: 36 years, 57% men) without overt heart failure were studied. We examined 12-lead electrocardiograms, 24-hour electrocardiographic Holter recordings, and treadmill exercise stress tests at baseline and after 12 months. Conventional electrocardiographic measurements, as well as contemporary indexes of depolarization and repolarization/dispersion of repolarization (QRS fragmentation; T peak-to-end; T peak-to-end/QT) were assessed. Moreover, we examined markers of autonomic dysfunction such as heart rate variability, and heart rate recovery after exercise testing. RESULTS: The electrocardiographic markers of atrial/ventricular depolarization and repolarization, as well as indexes of autonomic imbalance, were not significantly changed. However, the recorded supraventricular ectopic beats increased significantly. Paroxysmal atrial fibrillation (PAF) detection was greater in 12 months (4/47 at baseline vs. 8/47 at 12 months; P=0.38). However, 5/8 patients who were diagnosed with PAF at the second examination did not have the arrhythmia at the initial evaluation. Thus, PAF was present in a total of 9/47 (19%) TM patients. Notably, 3/9 of the patients were asymptomatic. The mean duration of PAF was 5±2 minutes and the mean number of these episodes was 8±2. CONCLUSION: TM patients have repolarization and autonomic function abnormalities that do not significantly change during a 12-month follow-up period. However, supraventricular ectopy and AF burden further evolve.

Association of fibroblast growth factor 21 with metabolic syndrome and endothelial function in children: a prospective cross-sectional study on novel biomarkers.

PURPOSE: Metabolic and cardiovascular disease prevention starting in childhood is critical for reducing morbidity later in life. In the present study, the association of novel biomarkers with metabolic syndrome (MS) and vascular function/structure indices of early atherosclerosis in children was investigated. METHODS: This was a prospective study of 78 children (8-16 years of age) grouped based on the presence or absence of MS. The serum biomarkers investigated included fibroblast growth factor 21 (FGF21), leptin, adiponectin, and insulinlike growth factor binding protein-1 (IGFBP1). Endothelial function and carotid atherosclerosis were assessed based on brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness, respectively. RESULTS: Children with MS (n=12) had higher levels of FGF21 (median [interquartile range]: 128 [76-189] pg/mL vs. 60 [20-98] pg/mL, P=0.003) and leptin (18.1 [11-34.8] pg/mL vs. 7.5 [1.9-16.5] ng/mL, P=0.003), and lower levels of IGFBP1 (1.5 [1.2-2.1] ng/mL vs. 2.3 [1.5-6] ng/mL, P=0.028) compared with children without MS. FMD inversely correlated with FGF21 (Spearman rho= -0.24, P=0.035) and leptin (rho= -0.24, P=0.002) in all children. The best cutoff value of FGF21 levels for MS diagnosis was above 121.3 pg/mL (sensitivity/specificity, 58/86%). Only FGF21 was significantly associated with the presence of MS after adjustment for body mass index, age, and sex (odds ratio per 10 pg/mL increase: 1.10 [95% confidence interval, 1.01-1.22]; P=0.043). CONCLUSION: Increased FGF21 levels were associated with the presence of MS and worse endothelial function in children. Larger studies are needed to evaluate the potential value of FGF21 as a biomarker that could predict future metabolic/cardiovascular disease at an early stage.

Association of fluid overload with patent ductus arteriosus during the first postnatal day.

BACKGROUND: Evidence examining the association of over-hydration during early life with haemodynamically significant patent ductus arteriosus (hsPDA) and other morbidities is limited. Our aim was to evaluate the association of fluid overload during the first postnatal day with hsPDA and common neonatal morbidities such as bronchopulmonary dysplasia in preterm infants. METHODS: A retrospective cohort study was conducted enrolling infants ≤30 weeks' gestation and ≤1500 grams' birth weight, admitted to a tertiary Neonatal Unit. We calculated the fluid balance and we estimated the incidence of infants with fluid overload ≥5% during the first postnatal day, evaluating any possible correlation with hsPDA. RESULTS: 103 infants of 27.3±1.6 weeks' gestation and 1009±225 grams' birth weight were enrolled; of whom 32 (31%) were diagnosed with HsPDA. Fluid overload during the first postnatal day was recorded in 42 infants (41%). Infants with fluid overload were diagnosed with hsPDA in 48%, compared to 20% of infants without fluid overload (p=0.004). No differences were recorded in the development of bronchopulmonary dysplasia or survival. Fluid overload of ≥5% was significantly correlated with hsPDA (r=0.37, p=0.003) and had an independent contribution to the risk of hsPDA (OR 1.17, 95% CI 1.05-1.58), irrespective of other perinatal factors. CONCLUSIONS: In preterm infants, fluid overload ≥5% is significantly associated with hsPDA, therefore, fluid management during the first postnatal day should be closely regulated.

The impact of dyslipidemia on early markers of endothelial and renal dysfunction in children.

BACKGROUND: Dyslipidemia has been associated with endothelial dysfunction in childhood. Impairment of renal function has been demonstrated in dyslipidemic adults. OBJECTIVE: The aim of this study was to assess markers of early endothelial and renal dysfunction in dyslipidemic children. METHODS: This was a cross-sectional study of 100 children with dyslipidemia and 100 age- and sex-matched control subjects without dyslipidemia aged 7-16 years. Renal dysfunction was assessed by measurement of serum creatinine and cystatin C levels, urinary beta 2-microglobulin levels, urinary albumin to creatinine (Alb:Cr) ratio, and by the estimated glomerular filtration rate (eGFR), based on serum creatinine or cystatin C. Endothelial dysfunction and early vascular changes were evaluated by ultrasound assessment of flow mediated dilation (FMD) of the brachial artery, and carotid intima-media thickness (cIMT), respectively. RESULTS: The markers of early renal dysfunction showed no difference between the dyslipidemic children and control subjects except for the urinary Alb:Cr ratio that was higher in the dyslipidemic children (median, 0.007 mg/mg vs 0.005 mg/mg, p = 0.004). The urinary Alb:Cr ratio was positively correlated with the triglyceride to high-density lipoprotein cholesterol ratio (r = 0.28, p = 0.013). FMD values were lower in the dyslipidemic children than in the control subjects (8.504 ± 4.73% vs 10.535 ± 4.35%, p = 0.004), but cIMT did not differ between groups. This decrease in FMD values was evident in children aged ≥10 years. FMD was independently associated with the level of lipoprotein (a) (beta = -0.29, p = 0.01). CONCLUSION: Among markers of endothelial and renal dysfunction investigated, FMD was found to be lower and the urinary Alb:Cr ratio higher in children with dyslipidemia.

Nine-year overview of dyslipidemia management in children with heterozygous familial hypercholesterolemia: a university hospital outpatient lipid clinic project in Northwestern Greece.

Background To assess the efficacy and safety of lipid-lowering treatment in children with heterozygous familial hypercholesterolemia (HeFH) aged ≤12 years attending a tertiary hospital-based outpatient lipid clinic. Methods Data in 318 children from the University Hospital of Ioannina (Northwestern Greece) Outpatient Lipid Clinic Project for Children and Adolescents with Dyslipidemia from March 2009 to December 2018 were analyzed. We assessed the efficacy and safety treatment alongside any possible predictors of the achievement of the treatment target. Results Of 318 children with hyperlipidemia, 72 were diagnosed having HeFH based on clinical criteria and genetic confirmation. Compared with non-familial hypercholesterolemia (non-FH) children, those with FH had a higher occurrence of positive family history of premature cardiovascular disease, and higher levels of total, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein (a) (Lp(a)). Treatment regimens included either atorvastatin 10-20 mg/day, rosuvastatin 5-10 mg/day, pitavastatin 2-4 mg/day monotherapy or in combination with ezetimibe. The treatment goal of LDL-C (<135 mg/dL, 3.5 mmol/L) was achieved in 69% of children treated. The achievement of the treatment targets correlated positively with male sex and inversely with the Dutch Lipid Clinic Network Score, baseline total, LDL-C and apoB levels. No clinically significant changes in liver or muscle-related laboratory tests were reported; no effect on growth or sexual maturation was noted. Conclusions This study confirms that lipid-lowering treatment in HeFH children initiated in the setting of a specialized tertiary hospital-based outpatient lipid clinic is efficacious and safe. Children of male sex and low baseline lipid values had a better achievement of treatment target.

Review shows that lipid disorders are associated with endothelial but not renal dysfunction in children.

AIM: We undertook this review to assess the effects of lipid metabolism abnormalities on endothelial and renal function in children. METHODS: A search of relevant literature published in English from January 1988 to May 2018 was performed, and this included randomised controlled trials, observational cohort studies, systematic reviews and case reports. RESULTS: The search process identified 2324 relevant studies and 29 were finally included. Noninvasive ultrasound markers of endothelial dysfunction, such as flow-mediated dilation and carotid intima-media thickness, were impaired in children with dyslipidaemia. Dietary interventions and statin therapy reversed the effects of dyslipidaemia on endothelial function in children. Most data from adult studies failed to prove a causative relationship between dyslipidaemia and renal disease progression or a beneficial effect of lipid-lowering treatment on renal outcomes. The limited paediatric data did not indicate dyslipidaemia as an independent risk factor for renal dysfunction, which was mainly estimated by cystatin C levels or proteinuria. Therefore, further investigation is needed to clarify a potential relationship. CONCLUSION: In view of limited available paediatric evidence, dyslipidaemia may be adversely associated with endothelial function. However, the association between lipid metabolism disorders and renal function in childhood needs to be further investigated.

Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.

Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms.

Electrocardiographic abnormalities and arrhythmic risk markers in adult patients with beta thalassemia major.

BACKGROUND: There seems to be a significant arrhythmia burden in ß-thalassemia major (TM) patients without overt cardiomyopathy. Apart from conventional electrocardiographic (ECG) and arrhythmic risk markers we studied novel markers of ventricular repolarization and autonomic imbalance both at rest and after exercise testing. METHODS: We studied 47 adult TM patients without systolic heart failure and 47 age and sex-matched healthy control subjects. The median age of the studied population was 36 [32-43] years, 57% men. Baseline demographic and clinical characteristics were recorded while 12-lead electrocardiograms, 24-hour ECG Holter recordings, and treadmill exercise stress tests were analyzed. RESULTS: TM patients exhibited increased QTc intervals in both 12-lead ECG recordings and in 24-hour Holter recordings. In addition, they had increased indexes of ventricular repolarization heterogeneity such as QT dispersion, and T peak-to-end/QT ratios. Furthermore, TM patients had decreased indexes of heart rate variability while the heart rate recovery after exercise was significantly attenuated compared to controls. Also, they had increased P wave and QRS duration while the QRS fragmentation was very prevalent. Finally, premature atrial extrasystoles and paroxysmal atrial fibrillation episodes were more frequent in TM patients. CONCLUSIONS: TM patients with preserved left ventricular systolic function have several ECG abnormalities including alterations in ventricular depolarization and repolarization. Also, cardiac autonomic dysfunction is evident in 24-hour ECG monitoring as well as in the recovery phase after exercise testing. The prognostic value of specific arrhythmic risk indexes in this setting remains to be elucidated.

Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21.

Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease.