[SARS-CoV-2 infections and the autonomic nervous system]. / SARS-CoV-2 Infektionen und das autonome Nervensystem.

Investigations of the heart rate variability (HRV) in an 11-year-old boy with multisystemic inflammation syndrome in children (MIS-C) and a 16-year-old girl with postural orthostatic tachycardia syndrome (POTS) after SARS-CoV­2 infections are presented. Results: The MIS­C is characterized by a maximum suppression of the HRV during ECG monitoring on the pediatric intensive care unit. After intravenous administration of immunoglobulins HRV supppression is rapidly reversible. The POTS is characterized by a heart rate increase of more than 40 bpm and the complete collapse of the HRV in the active standing test that can probably explain some chronic problems after SARS-CoV­2 infections. In the MIS­C patient we found autoantibodies against receptors of the autonomic nervous system. Summary: The examination of HRV in patients with COVID-19 are initial descriptions,which can enrich our knowledge of the pathophysiology of this new disease.

Alleviation of arrhythmia burden in children with frequent idiopathic premature ventricular contractions by omega-3-fatty acid supplementation.

BACKGROUND: Patients at our pediatric outpatient clinic were offered 24-h Holter electrocardiogram (ECG) before and after 3-month period of dietary supplementation with omega-3 fatty acids to monitor the effect on heart rate variability (HRV) and arrhythmias. METHODS: The study included 17 children (mean age: 11.6 ±â€¯4.9 years) with >1% premature ventricular contractions (PVC) at baseline. 24-h Holter ECG monitoring was performed before and after omega-3 fatty acid supplementation (mean duration: 143 days). RESULTS: Compared with 86 age-matched healthy control children, baseline HRV was significantly reduced and mean heart rate was significantly increased in children with frequent PVC. After omega-3-fatty acid supplementation, the mean heart rate decreased from 92.6 ±â€¯3.4 bpm to 83.9 ±â€¯9.9 bpm (p = 0.001), while global HRV showed a significant increase [standard deviation of all NN intervals (SDNN): 148.1 ±â€¯34.4 ms vs. 126.5 ±â€¯39.3 ms, p = 0.022)]. Enhanced vagal activity was indicated by significantly higher square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD) (42.3 ±â€¯12.6 vs. 33.2 ±â€¯14.8; p = 0.0003). PVC percentage significantly decreased by 45% (6.9 ±â€¯7.0% vs. 12.1 ±â€¯8.2%; p = 0.014). CONCLUSIONS: Omega-3-fatty acid supplementation caused a 45% reduction in frequent PVC in children with structurally healthy hearts. This antiarrhythmic effect was likely attributable to improved autonomic function, which is consistent with previous findings in children with obesity, attention deficit disorder, and short stature.

Different nutritional states and autonomic imbalance in childhood.

Autonomic imbalance, measured as heart rate variability (HRV), and an increased cardiovascular risk are described for overweight children, as well as for patients with anorexia nervosa. We investigate whether body mass index or actual caloric intake influences HRV. In our cross-sectional study, we compared HRV parameters for a healthy control group (n=52), anorexia nervosa patients (n=17), thin (n=18) and overweight children (n=19). Anorexia nervosa patients showed significantly lower heart rates at night (P<0.001) and significantly higher SDNN (standard deviation of all RR-intervals) (P<0.001 ), whereas overweight children showed an opposing pattern. SDNN and heart rate at night are highly correlated (r=0.89, R(2)=0.79, P<0.001). We conclude that not current body mass index but caloric intake determines HRV. Obesity and anorexia nervosa are characterized by a specific pattern of autonomic imbalance.

Beta-blocker therapy and hemophagocytic lymphohistiocytosis: a case report.

Objective. The aim of this paper is to describe a fatal case of hemophagocytic lymphohistiocytosis (HLH) in a patient with severe heart failure, who was treated with low-dose propranolol. Patient and Interventions. We report on a 7-month-old boy with Downs syndrome who was born with an unbalanced, left dominant atrioventricular septal defect and aortic coarctation. Despite coarctation repair and pulmonary artery banding he developed intractable heart failure and fever of unknown origin. Since he remained in heart failure he received a trial of low-dose propranolol to stabilize his cardiopulmonary status, which resulted in unexpected immunomodulatory effects. Measurements and Main Result. Immunoactivation was evidenced by high concentrations of procalcitonin, soluble CD 25, tumor necrosis factor alpha, and interleukin 6 and 8. Propranolol resulting in hepatic compromise as indicated by high lactate dehydrogenase and alanine aminotransferase levels. A therapeutic switch from propranolol to the beta(1)-receptor blocker metoprolol appeared to be instrumental in hemodynamic improvement and allowed discharge from hospital. However, the infant ultimately died from secondary inflammatory reactivation and intractable pulmonary obstructive disease. The autopsy results revealed HLH. Conclusion. Our case describes HLH secondary to heart failure and Downs syndrome. In this highly activated inflammatory state the beneficial hemodynamic effects of propranolol may be accompanied by immunomodulatory effects and the risk of acute liver failure. HLH occurs with a distinct pathophysiology, and specific treatment might be mandatory to increase the chance of survival.

NT-Pro-B-Type Natriuretic Peptide Levels in Infants with Failure to Thrive due to Caloric Deprivation.

Background. Brain natriuretic peptide and its inactive fragment N-terminal pro-BNP (N-BNP) are reliable markers of ventricular dysfunction in adults and children. We analyzed the impact of nutritional state on N-BNP levels in infants with failure to thrive (FTT) and in infants with severe heart failure (HF). The purpose of this study was to compare N-BNP levels in infants with FTT with infants with severe HF and healthy controls. Methods. In a retrospective cohort study, we compared N-BNP levels from all consecutive infants with FTT and bodyweight below the tenth percentile (caloric deprivation (CD) group) to infants with severe HF. Reference values from infants between 2 and 12 month were taken from the literature and healthy infants. Results. Our results show that infants with FTT (n = 15) had significantly (P < .001) elevated N-BNP values compared with the healthy infants (n = 23), 530 (119-3150) pg/mL versus 115 (15-1121) pg/mL. N-BNP values in this CD group are comparable to the median value of infants with severe HF (n = 12) 673 (408-11310) pg/mL. There is no statistical significant difference in age. Conclusion. Nutritional state has an important impact on N-BNP levels in infants with FTT. We could show comparable levels of N-BNP in infants with FTT and infants with severe HF.

[The technique of outflow tract reconstruction in patients with tetralogy of Fallot influence the morbidity 3 decades after repair]. / Die Technik der Ausflussbahnrekonstruktion bei Fallotscher Tetralogie beeinflusst die Morbidität der Patienten nach drei Jahrzehnte nach einer Korrekturoperation.

The purpose of this study was to examine long-term results of different surgical techniques in patients with tetralogy of Fallot considering their morbidity. We analyzed the data of 74 patients 24.5 +/- 3 years after surgical repair in childhood to evaluate their clinical status, maximal exercise capacity, medication and frequency of reoperations. We compared two groups of patients according to the surgical techniques employed: 1) TAP group (Trans anular Patch, n = 41) in which ventricular septal defects were closed with a Dacron patch, the right ventricular outflow was reconstructed by resection of the partial extension of the infundibular septum and transanular patch repair was performed because of hypoplastic pulmonary valve. 2) nonTAP group (33) in which no transanular patch repair was necessary. Most of the patients described their health as "good". 94% of the nonTAP group and 71% of TAP group were in NYHA class I. The rest were in NYHA class II. Despite the good clinical classification we found a reduced cardiopulmonary exercise capacity in all patients. More than 50% in the TAP group took medicine because of congestive heart failure and/or arrhythmia, which was present 3-times more often compared with the nonTAP group. Furthermore, 50% of TAP group patients had at least one reoperation during the follow- up: by comparison 5-times more often than the nonTAP group. These data show that the long-term outcome and morbidity of the patients after repair is closely related to the type of the surgical technique employed.

The pathogenesis of heart failure in infants with congenital heart disease.

BACKGROUND: The clinical symptoms of heart failure in infants with left-to-right shunts are thought to be explained by well-known hemodynamic disturbances such as pulmonary hypertension and overcirculation, but previous studies have not, thus far, found the expected correlations with hemodynamic and clinical parameters. Based on the neurohormonal model of heart failure, we hypothesised that the clinical symptoms of infants with left-to-right shunts are also related to neurohormonal disorders. METHODS: We compared various neurohormonal and hemodynamic parameters measured invasively in 70 infants with left-to-right shunts to the respiratory rate and gain in weight over a corresponding period of time. Heart rate correlated significantly with respiratory rate (r = 0.62***, p < 0.001) and gain in weight (r = -0.31*, p = 0.015), but more conventional measures of severity, such as the ratio of pulmonary to systemic flows, failed to show comparable correlations with clinical symptoms. Respiratory rate was related to levels of norepinephrine (r = 0.47***, p < 0.001) and plasma renin activity (r = 0.65***, p < 0.001). The important impact of autonomic imbalance on respiratory rate was underlined by an analysis of variability of heart rate in 26 infants that showed significantly reduced values for the domains of time and frequency. We were not able to find a conclusive multiple regression model with which to explain the symptom "failure to thrive". CONCLUSIONS: A increased heart rate, reduced variability in heart rate, and elevated levels of norepinephrine and renin are significant predictors of clinical symptoms such as tachypnea in infants with congenital cardiac malformations. The neurohormonal hypothesis, in which heart failure is interpreted not only as a hemodynamic derangement but also as a neurohormonal disorder, may be valid for infants with congenital cardiac malformations.

Endogenous nitric oxide and soluble tumor necrosis factor receptor levels are enhanced in infants with congenital heart disease.

OBJECTIVE: This study was designed to investigate cytokine and nitric oxide levels in pediatric patients suffering from chronic heart failure and to investigate effects of beta-blocker treatment on these levels. PATIENTS: Fifteen infants with heart failure resulting from left-to-right shunts with pulmonary overcirculation were compared with 11 infants with cyanotic heart defects with reduced pulmonary blood flow. Four of these patients were finally treated with the beta-blocker propranolol. MEASUREMENTS: Endogenous nitric oxide production was determined by measuring total plasma nitrite/nitrate (Griess method), and levels of soluble tumor necrosis factor receptors type 1 and type 2 (TNF-R1 and TNF-R2, respectively) were measured by commercially available enzyme-linked immunosorbent assay. MAIN RESULTS: In infants with left-to-right shunts, soluble tumor necrosis factor receptor levels were significantly elevated as compared with infants with cyanosis (TNF-R1: 1.7 +/- 0.5 vs. 0.8 +/- 0.3 ng/mL; p =.0003; TNF-R2: 8.1 +/- 4.0 vs. 5.1 +/- 3.2 ng/mL; p =.049). In addition, we found a significant correlation between nitrate/nitrite levels and TNF-R1 (r =.70; p =.0001) or TNF-R2 (r =.62; p =.0013), respectively. Furthermore, the tumor necrosis factor receptor levels in four children after beta-blocker treatment were lower as compared with levels before beta-blocker treatment. CONCLUSIONS: Immune mechanisms, such as cytokine or nitric oxide production, may be involved in pathogenesis of heart failure in children, and may contribute to the beneficial effects of beta-blocker treatment observed in these patients.

Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants treated with propanol.

AIM: Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure. METHODS AND RESULTS: We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001). CONCLUSION: Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation.

Activity of the renin-angiotensin-aldosterone and sympathetic nervous system and their relation to hemodynamic and clinical abnormalities in infants with left-to-right shunts.

We studied neurohormonal, clinical and invasively measured hemodynamic data of 47 infants with left-to-right shunts and varying degrees of congestive failure. When referred to a clinical heart failure score, plasma renin activities (r=0.71) and norepinephrine levels (r=0.43) are significantly increased. Arterial hypotension seems to be the hemodynamic trigger of renin release (r=-0.72), but not decreased systemic cardiac index (r=-0.43), the magnitude of the left-to-right shunt (r=0.33) or a reduced ejection fraction (r=0.12). These data indicate neurohormonal activation in infants with left-to-right shunts with preserved myocardial function is similar to the activation in adults with heart failure secondary to myocardial pump failure. These findings have to be considered for optimal medical treatment of these infants with angiotensin-converting enzyme inhibitors or beta-blockers.

[Electrocardiographic signs of autonomic imbalance in infants with congenital heart defects]. / Elektrokardiographische Zeichen der autonomen Imbalance bei Säuglingen mit angeborenen Herzfehlern.

Infants with congenital heart disease (CHD) and heart failure have elevated plasma norepinephrine levels (NE) as a sign for sympathetic activation. We analysed ECGs of 64 infants with CHD and found normal heart rates on average in four groups split up according to their NE. Mean heart rate in Holter ECGs was significantly reduced in infants with low NE (below 350 ng/l) but normal in the other groups (NE < 350 ng/l: 121 +/- 10/min; NE = 350-700 ng/l: 139 +/- 11/min; NE = 700-1300 ng/l: 142 +/- 13/min; NE > 1300 ng/l: 135 +/- 12/min). An analysis of heart rate variability in a subgroup of 25 infants showed significantly reduced values in patients with elevated NE in comparison to 70 healthy infants. Significantly reduced frequency domain measures in infants with elevated NE but also normal NE are evidence for a high diagnostic sensitivity of an analysis of heart rate variability for autonomic imbalance with sympathetic activation and parasympathetic withdrawal in infants with CHD.

Pathogenetic mechanisms of venous congestion after the Fontan procedure.

BACKGROUND: The hemodynamic status after a Fontan type procedure for definitive palliation of functionally univentricular hearts is dominated by a high central venous pressure, which seems to be one of several factors responsible for venous congestion appearing as a frequent complication in the early and late postoperative course. The purpose of our study was to find other hemodynamic parameters correlating with the presence of venous congestion and effusions in these patients. METHODS: We compared the hemodynamic data of 18 patients who had an uneventful long-term course after a Fontan type procedure with the respective data of 10 patients who developed symptoms of venous congestion in the immediate postoperative period. Based on a theoretical model, we developed an algorithm to calculate mean hydrostatic capillary pressure from mean arterial pressure, systemic vascular resistance index and central venous pressure. RESULTS: Pulmonary vascular resistance index (2.1 +/- 1.0 mmHg L-1 min m2), mean left atrial pressure (9.7+/-4.0 mmHg) and cardiac index (3.6+/-0.6 l/min/m2) are mainly normal in patients with venous congestion in the immediate postoperative period, but mean hydrostatic capillary pressure is significantly higher compared to patients without venous congestion (24.3+/-3.1 vs 18.3+/-4.0 mmHg). Lower mean hydrostatic capillary pressures in these patients are due to a highly significant increase of systemic vascular resistance index (18.6+/-4.2 versus 33.6+/-6.6 mmHg L-1 min m2) and a concomitant decrease of cardiac index to 2.4+/-0.3 l/min/m2. CONCLUSIONS: The increase of mean hydrostatic capillary pressure, caused by high central venous pressures but also by relatively low systemic vascular resistance indexes, seems to be the hemodynamic key parameter responsible for venous congestion and effusions in patients after a Fontan type procedure in the immediate postoperative period.

Interleukin-1 and related proteins in cardiovascular disease in adults and children.

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.

Effectiveness of low dose captopril versus propranolol therapy in infants with severe congestive failure due to left-to-right shunts.

UNLABELLED: To evaluate the therapeutical effects of the angiotensin converting enzyme inhibitor Captopril to the beta-blocker Propranolol in infants with congestive failure due to pulmonary overcirculation, we retrospectively analysed clinical, neurohormonal and hemodynamic data in 22 infants, 11 of whom were treated with Captopril (Group 1), 11 with Propranolol (Group 2). Age, weight, number of palliative operations, plasma renin activities and pulmonary to systemic flow ratios (3.5 vs. 3.5) were not significantly different prior to Captopril or Propranolol therapy. If treatment with digoxin and diuretics did not succeed, the infants were additionally treated with Captopril (1 mg/kg) for a mean of 7.4 months, or with 1.9 mg/kg Propranolol for 9.2 months. RESULTS: 1 mg/kg Captopril did not effectively suppress angiotensin converting enzyme in the steady state at trough level (92+/-52 vs. 87+/-50 nmol/min/ml). In the Propranolol group, the clinical heart failure score (2.6+/-1.5 vs. 7. 4+/-2.5) and plasma renin activities (14+/-10 vs. 101+/-70 ng/ml/h) were significantly lower, compared to the Captopril group. Length of hospital stay (23+/-9 vs. 52+/-24 days) was lower and weight gain (126+/-38 vs. 86+/-84 g/week) was higher within 3 months after starting Propranolol therapy. Significantly lower left atrial pressures (6.2+/-2.2 vs. 13.4+/-9.2 mmHg) and lower endiastolic ventricular pressures (7.6+/-2.5 vs. 12.6+/-4.0 mmHg) during pre-operative cardiac catheterization indicated a better diastolic ventricular function under chronic Propranolol treatment. CONCLUSION: Although high dose Captopril was not evaluated in this study, when compared to patients on low Captopril dosages, infants who received Propranolol treatment showed improvement in heart failure scores, shorter lengths of hospital stay, lower plasma renin activities and better diastolic ventricular functions.

[Circulatory failure in children with left-to-right shunt in the framework of congenital heart defects: pathophysiology and therapeutic results]. / Kreislaufinsuffizienz bei Kindern mit Links-rechts-Shunts im Rahmen angeborener Herzfehler--Pathophysiologie und therapeutische Konsequenzen.

In children with large left-to-right shunts secondary to congenital heart defects the imbalance between the pulmonary and systemic perfusion may lead to circulatory congestion with clinical signs similar to those of heart failure. The circulatory function in this state was evaluated by using the invasive measurements performed during cardiac catheterisations in n = 64 young patients with ventricular septal defect (n = 56) or complete atrioventricular septal defect (n = 8) aging 0.1-23.7 years (median 1.1 years). The mean shunt ratio was Qp/Qs = 2.4 (range 1-8). With increasing shunt ratio the pulmonary perfusion raised (r = 0.84), but the systemic output dropped significantly (r = -0.77) while the total cardiac output (Qp + Qs) increased slightly not exceeding 141/min/m2. In infants, the systemic hypoperfusion affects the hemoglobin content: Hb = 14.9-1.01 x Qs, r = 0.63, p < 0.01. This may be due to the diminished oxygen extraction reserve of 46%. With dropping systemic output, the vascular resistance increases and the mean aortic pressure (MAP) remains normal. The actual pressure values layed near to the curve of the normal aortic pressure calculated as MAP = Qs x Rs. This pressure-flow-resistance diagram was used to interpret the effects of vasodilators established by 7 studies: ACE-Inhibitors, Hydralazine, and Na-Nitroprusside reduce the vascular resistance effectively but induce hypotension, because the systemic output fails to increase. In the chronic circulatory congestion secondary to a large intracardiac left-to-right shunt the pulmonary perfusion increases with the shunt ratio but the systemic output decreases and the total cardiac output is limited to a maximum of 141/min/m2. In this state vasodilators cause systemic hypotension thus offering no acceptable therapeutic option.