Search

Background Myocarditis is an inflammatory disease of the heart muscle with a wide range of clinical presentations, from asymptomatic to cardiogenic shock and death. Although acute myocarditis is rare in pediatric population, it is caused by common viral infections, like parvovirus B19 or enteroviruses. Limited scientific evidence supports the existence of a genetic background that could underlay the susceptibility to virus-induced myocarditis. Purpose The aim of the present study was to identify mutations in genes associated with cardiomyopathies, that could possibly underly acute myocarditis in pediatric patients with biopsy-proven parvovirus B19 infection, verified by real time PCR. Methods Nine pediatric patients presented in our center with acute myocarditis were genotyped with next generation sequencing using Clinical Exome Solution kit (Sophia Genetics) covering 4493 disease-related genes. Variant pathogenicity was accessed according to guidelines by American College of Medical Genetics (2015). Results Genetic analysis revealed that three of the nine patients were found positive for pathogenic/likely pathogenic mutations in TTR, ABCC6 and SLC22A5 genes. The patient that carried the SLC22A5 variant initially received telbivudine and her ejection fraction was improved from 20% to 45%. Genetic test results suggested that the patient may suffer from mild L-carnitine deficiency. Oral supplementation with high dose of L-carnitine during one month period improved dramatically her EF to normal (65%). The patient that carried the ABCC6 mutation, also carried a variant of unknown significance in MYH7 gene. Four patients carried variants of unknown significance. The variants of unknown significance detected in MYBPC3, SCN5A, and MYH7 genes are of particular interest since they accumulate evidence of pathogenicity. Two patients did not harbor any mutations. Conclusion A significant proportion of rare variants in genes associated with cardiomyopathies has been identified in a small cohort of pediatric patients with parvovirus-induced acute myocarditis. The findings of our study, although limited, support the existence of a genetic background that could function as a predisposing factor influencing the clinical course of the disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Onassis Foundation

ObjectiveRelative corticosteroid insufficiency may be common in critically ill patients and is associated with a poor outcome; however, the response of the hypothalamic–pituitary–adrenal (HPA) axis in nursed patients is not known. Our aim was to evaluate the response of HPA axis to the severity of illness in non-critically ill nursed (NCIN) patients and the clinical outcome.Subjects and methodsFifty-six nursed patients who were divided into four groups (stroke, mild disease, sepsis and severe sepsis) as well as a control group (n=15) were studied. At admission (day 1), cortisol and ACTH were measured and a low-dose (1 μg) corticotrophin test was performed, followed 2 h later by a standard-dose (250 μg) corticotrophin test. Diurnal variation of cortisol was obtained on day 2. A second identical set of low-dose and standard-dose corticotrophin tests were performed on day 5 or 6 (recovery phase).ResultsIn patients with stroke and severe sepsis, cortisol had the highest values and its diurnal variation was abolished. Dissociation of ACTH and cortisol was found in all patients.The Δmax of cortisol after the 1-μg corticotrophin test did not differ among the groups, while after the 250-μg corticotrophin test, it was borderline higher in controls. The ratio of responders (Δmax of cortisol ≥9 μg/dl) to non-responders after 1- or 250-μg corticotrophin test did not differ among patients and controls. All patients had a good outcome without glucocorticoid treatment.ConclusionsDepending on the severity of illness, mild alterations in the HPA axis occurred. However, relative corticosteroid insufficiency was not confirmed in NCIN patients.

To evaluate right ventricular function in patients with beta-thalassaemia major and congestive heart failure. Background In patients with beta-thalassaemia major a high incidence of cardiac involvement still exists despite improved prognosis with chelation therapy. Development of severe right heart failure is common and has been attributed to pulmonary hypertension secondary to lung haemochromatosis. However, the possibility of direct right ventricular myocardial involvement in the absence of significant pulmonary hypertension has not been adequately investigated.Twenty-nine consecutively screened patients with beta-thalassaemia major and congestive heart failure were investigated by Doppler echocardiography, right ventricular first-pass radionuclide examination and cardiac catheterization. Haemodynamic data were obtained both before and after volume loading. A control group of 39 patients with beta-thalassaemia major, free from cardiac disease, and matched for age, gender, body surface area and heart rate was used for comparison. A subset of the control thalassaemic group (n=15) underwent both radionuclide and haemodynamic assessment.The majority of patients were on non-optimal chelation therapy. Only two of 29 patients were found to have cor pulmonale. One other patient suffered from constrictive pericarditis. A restrictive filling pattern in both ventricles and left ventricular systolic dysfunction were evident in the other 26 patients. Pulmonary artery pressure (systolic, 33+/-8 vs 27+/-5 mmHg, P0.05) and pulmonary vascular resistance (114+/-56 vs 65+/-29 dynes. s. cm(-5), P0.01) were only mildly elevated in the heart failure group. After volume challenge, cardiac output remained unchanged although the increments of ventricular filling pressures were significant (Deltaright atrial: 4.8+/-2.2 mmHg, P0.05; Deltapulmonary capillary wedge: 5.6+/-2.9 mmHg, P0.05) and correlated with each other (r=0.69;P0.001) in heart failure patients, suggesting pericardial constraint and ventricular interaction. In these patients compared with the control thalassaemic group, a lower right ventricular ejection fraction (29%+/-9 vs 59%+/-6, P0.0001) without correlation with pulmonary artery pressures was found. Haemodynamically significant right ventricular dysfunction defined as mean right atrial pressure10 mmHg and ratio of mean right atrial-to-capillary wedge pressure0.8 was evident in 15 of the 26 patients (58%), all with severe symptoms, representing three fourths of the patients in functional class III and IV. Simultaneous pressure recordings in six of these 15 patients showed equalization of ventricular end-diastolic pressures within 5 mmHg.The majority of patients with beta-thalassaemia major and severe congestive heart failure demonstrated a unique haemodynamic pattern similar to that described in predominant right ventricular infarction, indicating severe right ventricular cardiomyopathy in addition to left ventricular dysfunction. The incidence of cor pulmonale as a cause of right heart failure seems to be much lower than previously hypothesized.

OBJECTIVE: Patients with beta-thalassemia frequently develop primary hypothyroidism and other endocrine disorders due to iron overload. We studied whether administration of excess iodide to patients with apparently normal thyroid function could uncover an underlying thyroid disease. DESIGN AND METHODS: Twenty-five patients, 10 prepubertal (mean age 11+/-3 years) and 15 adults (mean age 23+/-5 years) with normal thyroid hormone and TSH levels, a normal response of TSH to TRH and negative thyroid peroxidase antibodies received 20mg iodide three times daily for three weeks, and thyroid hormone and TSH levels were measured weekly during, and for three weeks after, iodide administration and every 3 months thereafter for the next 5 years. RESULTS: During iodide administration there was a significant decrease in thyroid hormone concentrations which remained within normal levels, and a significant increase in TSH concentrations which in 14 out of 25 (56%) patients reached the hypothyroid level. Baseline TSH values were higher in those patients who developed subclinical hypothyroidism (2.31+/-0.71mU/l vs 1. 34+/-0.64mU/l, P=0.0016). Subclinical hypothyroidism developed in 70% of prepubertal and in 47% of adult patients. Serum ferritin was elevated in all patients. Nine of the fourteen patients (64.3%) who developed subclinical hypothyroidism during iodide administration developed hypothyroidism during the 5-year follow-up compared with only one of the eleven patients with a normal response to iodide (P=0.004). CONCLUSIONS: Patients with beta-thalassemia should not be exposed to excess iodide due to increased sensitivity to its inhibitory effects on thyroid function. The susceptible individuals frequently develop permanent hypothyroidism in the following years.

Brief hyperventilation is occasionally accompanied by repolarization abnormalities in subjects without apparent heart disease. However, the effect of prolonged hyperventilation on repolarization abnormalities is not clearly defined. We analysed the repolarization abnormalities induced by prolonged hyperventilation, correlated with hyperventilation induced haemodynamic changes and exercise test results and assessed the effect on them of age, gender, smoking and hypertension. Prolonged hyperventilation (overbreathing at least 30 respirations/min for 5 min and 10 min recovery) was performed in 474 healthy volunteers (269 men, 205 women) 42.6 +/- 13.5 years old. The electrocardiogram was analysed for transient ST depression or T-wave inversion. Repolarization abnormalities were observed in 72 subjects, 47 men (17.5%) and 25 women (12.2%). Age, gender, smoking and hypertension did not influence the overall incidence of repolarization abnormalities. ST depression was more frequently observed in women (4.4 vs 0.7%, P < 0.01), while T wave inversion from negative to positive was more frequent in men (8.9 vs 2.4%, P < 0.006). All subjects with ST depression were non-smokers (4.1% of the non-smokers, P < 0.003 compared to smokers). Repolarization abnormalities occurred usually (80.5%), but not exclusively, within the first hyperventilation minute. Subjects with repolarization abnormalities developed higher heart rate change with hyperventilation than those without repolarization abnormalities (29.2 +/- 13.1 vs 24.2 +/- 12.7, P < 0.002). A positive exercise test was observed in 45.4% of subjects with hyperventilation induced ST depression but only in 13.1% of subjects with T-wave changes, P < 0.02. Repolarization abnormalities are not uncommon during prolonged hyperventilation. Hear rate change affects the occurrence of repolarization abnormalities, while gender and smoking influence the type of repolarization abnormalities. ST depression but not T-wave inversion during hyperventilation is associated with a positive exercise test. Increased understanding about hyperventilation-induced repolarization abnormalities could affect use of the method in the clinic, either as a provocation test or as a complement to the interpretation of the exercise test.

BACKGROUND: Stimulated hyperinsulinaemia is observed in some patients with syndrome X, defined as angina, positive stress test and normal coronary arteriography, and may be involved in the pathogenesis of the syndrome. An increased sympathetic response to exercise may also be pathogenetically involved. However, the diagnostic value of hyperinsulinaemia as a marker of this syndrome has not been defined. METHODS: We determined blood glucose and immunoreactive insulin during fasting, at 60 and 120 min after a glucose load of 75g in 21 patients (eight men, 13 women, 53.9 +/- 7.1 years old) with syndrome X and in 21 healthy volunteers matched to the patients for age, sex and body mass index (eight men, 13 women, 51.6 +/- 9.3 years old). Insulin values were related to the rate-pressure product increase at first exercise stage. RESULTS: The glucose values as well as the insulin values during fasting were similar in syndrome X patients and in controls. However, significantly higher insulin values (mU/l) were observed at 60 (P < 0.01) and 120 min (P < 0.005) in syndrome X patients (median 75.5 and 52, range 43-290 and 6.1-212, respectively) than in controls (median 47.5 and 24.5, range 8-195.6 and 5.2-164, respectively). A considerable overlap of insulin values, however, was observed between the two groups, with abnormal values even during fasting. For a specificity of 95%, an abnormal insulin value had a sensitivity of between 19 and 24% and a diagnostic accuracy of 57-60%. A significant positive correlation was found between insulin levels after the glucose load and the rate-pressure product increment with exercise (60 min, r = 0.60; 120 min, r = 0.65). CONCLUSION: Hyperinsulinaemia may be pathogenetically involved in syndrome X patients, in close relation to the higher sympathetic drive that characterizes this syndrome. However, the wide range of insulin values, frequently overlapping with normal values, limits the usefulness of this abnormality as a marker of the syndrome.