Factors Associated With Sinoatrial Reinnervation After Heart Transplantation.

Background: Factors associated with sympathetic and parasympathetic sinoatrial reinnervation after heart transplantation (HTx) are inadequately studied. Methods: Fifty transplant recipients were examined at 7 to 12 wk (index visit), 6, 12, 24, and 36 mo after HTx. Supine rest heart rate variability in the low-frequency (LF) domain (sympathetic and parasympathetic sinoatrial reinnervation) and the high-frequency (HF) domain (parasympathetic sinoatrial reinnervation) were measured repeatedly and related to selected recipient, donor, and perisurgical characteristics. We primarily aimed to identify index visit factors that affect the sinoatrial reinnervation process. Secondarily, we examined overall associations between indices of reinnervation and repeatedly measured recipient characteristics to generate new hypotheses regarding the consequences of reinnervation. Results: LF and HF variability increased time dependently. In multivariate modeling, a pretransplant diagnosis of nonischemic cardiomyopathy (P = 0.038) and higher index visit handgrip strength (P = 0.028) predicted improved LF variability. Recipient age, early episodes of rejection, and duration of extracorporeal circulation were not associated with indices of reinnervation. Study average handgrip strength was positively associated with LF and HF variability (respectively, P = 0.005 and P = 0.029), whereas study average C-reactive protein was negatively associated (respectively, P = 0.015 and P = 0.008). Conclusions: Indices of both sympathetic and parasympathetic sinoatrial reinnervation increased with time after HTx. A pretransplant diagnosis of nonischemic cardiomyopathy and higher index visit handgrip strength predicted higher indices of mainly sympathetic reinnervation, whereas age, rejection episodes, and duration of extracorporeal circulation had no association. HTx recipients with higher indices of reinnervation had higher average handgrip strength, suggesting a link between reinnervation and improved frailty. The more reinnervated participants had lower average C-reactive protein, suggesting an inhibitory effect of reinnervation on inflammation, possibly through enhanced function of the inflammatory reflex. These potential effects of reinnervation may affect long-term morbidity in HTx patients and should be scrutinized in future research.

Preoperative versus postoperative survival in patients with univentricular heart: a nationwide, retrospective study of patients born in 1990-2015.

OBJECTIVES: Few data exist on mortality among patients with univentricular heart (UVH) before surgery. Our aim was to explore the results of intention to perform surgery by estimating preoperative vs postoperative survival in different UVH subgroups. DESIGN: Retrospective. SETTING: Tertiary centre for congenital cardiology and congenital heart surgery. PARTICIPANTS: All 595 Norwegian children with UVH born alive from 1990 to 2015, followed until 31 December 2020. RESULTS: One quarter (151/595; 25.4%) were not operated. Among these, only two survived, and 125/149 (83.9%) died within 1 month. Reasons for not operating were that surgery was not feasible in 31.1%, preoperative complications in 25.2%, general health issues in 23.2% and parental decision in 20.5%. In total, 327/595 (55.0%) died; 283/327 (86.5%) already died during the first 2 years of life. Preoperative survival varied widely among the UVH subgroups, ranging from 40/65 (61.5%) among patients with unbalanced atrioventricular septal defect to 39/42 (92.9%) among patients with double inlet left ventricle. Postoperative survival followed a similar pattern. Postoperative survival among patients with hypoplastic left heart syndrome (HLHS) improved significantly (5-year survival, 42.5% vs 75.3% among patients born in 1990-2002 vs 2003-2015; p<0.0001), but not among non-HLHS patients (65.7% vs 72.6%; p=0.22)-among whom several subgroups had a poor prognosis similar to HLHS. A total of 291/595 patients (48.9%) had Fontan surgery CONCLUSIONS: Surgery was refrained in one quarter of the patients, among whom almost all died shortly after birth. Long-term prognosis was largely determined during the first 2 years. There was a strong concordance between preoperative and postoperative survival. HLHS survival was improved, but non-HLHS survival did not change significantly. This study demonstrates the complications and outcomes encountering newborns with UVH at all major stages of preoperative and operative treatment.

Predictors of Hypertension Development 1 Year After Heart Transplantation.

BACKGROUND: Hypertension after heart transplantation (HTx) is common. We investigated predictors of and mechanisms for hypertension development during the first year after HTx, with particular attention toward immunosuppressive agents, reinnervation processes, and donor/recipient sex. METHODS: Heart transplant recipients (HTxRs) were consecutively enrolled 7 to 12 wk after surgery and followed prospectively for 12 mo. Ambulatory blood pressure recordings and autonomic cardiovascular control assessments were performed at baseline and follow-up. Possible predictors of posttransplant hypertension development were investigated in bivariate linear regression analyses followed by multiple regression modeling. RESULTS: A total of 50 HTxRs were included; 47 attended the follow-up appointment at 12 mo. Mean systolic and diastolic blood pressure increased significantly during the observational period (systolic blood pressure from 133 to 139 mm Hg, P = 0.007; diastolic blood pressure from 81 to 84 mm Hg, P = 0.005). The blood pressure increment was almost exclusively confined to HTxRs with a female donor heart, doubling the cases of systolic hypertension (from 6 to 13/14; 46% to 93%, P = 0.031) and diastolic hypertension (from 7 to 14/14; 54% to 100%, P = 0.031) in this subgroup. Autonomic cardiovascular control assessments suggested tonically constricted resistance and capacitance vessels in recipients with female donor hearts. Immunosuppressive agents and reinnervation markers were not associated with hypertension development. CONCLUSIONS: Blood pressures increase during the first year after HTx, with female donor sex as a strong predictor of recipient hypertension development. The underlying mechanism seems to be enhanced peripheral vasoconstriction caused by attenuated cardiovascular homeostasis capabilities. Further studies are needed to confirm the results.

Circulatory Response to Rapid Volume Expansion and Cardiorespiratory Fitness in Fontan Circulation.

The role of dysfunction of the single ventricle in Fontan failure is incompletely understood. We aimed to evaluate hemodynamic responses to preload increase in Fontan circulation, to determine whether circulatory limitations in different locations identified by experimental preload increase are associated with cardiorespiratory fitness (CRF), and to assess the impact of left versus right ventricular morphology. In 38 consecutive patients (median age = 16.6 years, 16 females), heart catheterization was supplemented with a rapid 5-mL/kg body weight volume expansion. Central venous pressure (CVP), ventricular end-diastolic pressure (VEDP), and peak systolic pressure were averaged for 15‒30 s, 45‒120 s, and 4‒6 min (steady state), respectively. CRF was assessed by peak oxygen consumption (VO2peak) and ventilatory threshold (VT). Median CVP increased from 13 mmHg at baseline to 14.5 mmHg (p < 0.001) at steady state. CVP increased by more than 20% in eight patients. Median VEDP increased from 10 mmHg at baseline to 11.5 mmHg (p < 0.001). Ten patients had elevated VEDP at steady state, and in 21, VEDP increased more than 20%. The transpulmonary pressure difference (CVP‒VEDP) and CVP were consistently higher in patients with right ventricular morphology across repeated measurements. CVP at any stage was associated with VO2peak and VT. VEDP after volume expansion was associated with VT. Preload challenge demonstrates the limitations beyond baseline measurements. Elevation of both CVP and VEDP are associated with impaired CRF. Transpulmonary flow limitation was more pronounced in right ventricular morphology. Ventricular dysfunction may contribute to functional impairment after Fontan operation in young adulthood.ClinicalTrials.gov identifier NCT02378857.

Strong evidence for parasympathetic sinoatrial reinnervation after heart transplantation.

BACKGROUND: Heart transplantation (HTx) surgically denervates the heart. We examined indices of sinoatrial reinnervation, with emphasis on (1) the occurrence and timing of parasympathetic reinnervation, and (2) the consequences of reinnervation for heart rate (HR) responsiveness and arterial baroreceptor sensitivity. METHODS: Fifty HTx recipients were prospectively followed for 36 months after surgery. Hemodynamic variables and heart rate variability were continuously recorded at supine rest, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. RESULTS: Suggesting parasympathetic reinnervation: at baseline rest, root of the mean squared differences of successive RR intervals increased from median 3.9(5.9) to 7.1(5.1) ms (p < 0.001); high-frequency power increased from 4.0(12) to 5.7(18.9) ms2 (p = 0.018); and baroreceptor sensitivity increased from 0.04(0.36) to 1.3(2.4) ms/mmHg (p < 0.001). Suggesting sympathetic reinnervation: at baseline rest low-frequency power increased from 0.49(2.5) to 7.5(18.1) ms2 (p < 0.001); and HR responses to sympathetic stimulation during (1) head-up tilt increased from 1.9(4.2) to 9.1(8.2) bpm (p < 0.001), (2) Valsalva increased from 1.6(1.4) to 8.3(10.8) bpm (p < 0.001) and (3) handgrip increased from 0.3(0.6) to 1.9(5.1) bpm (p < 0.001). Signs of sympathetic reinnervation emerged within 6 months, while signs of parasympathetic reinnervation emerged by 24 months. CONCLUSIONS: Root of the mean squared differences of successive RR intervals, high-frequency and low-frequency variability, HR responsiveness and arterial baroreflex sensitivity all increased after HTx, suggesting functional parasympathetic and sympathetic sinoatrial reinnervation. Accordingly, the pathological regulatory state present in heart transplant recipients, which is responsible for a host of functional and clinical abnormalities, is being partially offset over time by restored autonomic control of the heart in many heart transplant recipients.

The Oslo Ischaemia Study: cohort profile.

PURPOSE: The Oslo Ischaemia Study was designed to investigate the prevalence and predictors of silent coronary disease in Norwegian middle-aged men, specifically validating exercise electrocardiography (ECG) findings compared with angiography. The study has been important in investigating long-term predictors of cardiovascular morbidity and mortality, as well as investigating a broad spectrum of epidemiological and public health perspectives. PARTICIPANTS: In 1972-1975, 2014 healthy men, 40-59 years old, were enrolled in the study. Comprehensive clinical examination included an ECG-monitored exercise test at baseline and follow-ups. The cohort has been re-examined four times during 20 years. Linkage to health records and national health registries has ensured complete endpoint registration of morbidity until the end of 2006, and cancer and mortality until the end of 2017. FINDINGS TO DATE: The early study results provided new evidence, as many participants with a positive exercise ECG, but no chest pain ('silent ischaemia'), did not have significant coronary artery stenosis after all. Still, they were over-represented with coronary disease after years of follow-up. Furthermore, participants with the highest physical fitness had lower risk of cardiovascular disease, and the magnitude of blood pressure responses to moderate exercise was shown to influence the risk of cardiovascular disease and mortality. With time, follow-up data allowed the scope of research to expand into other fields of medicine, with the aim of investigating predictors and the importance of lifestyle and risk factors. FUTURE PLANS: Recently, the Oslo Ischaemia Study has been found worthy, as the first scientific study, to be preserved by The National Archives of Norway. All the study material will be digitised, free to use and accessible for all. In 2030, the Oslo Ischaemia Study will be linked to the Norwegian Cause of Death Registry to obtain complete follow-up to death. Thus, a broad spectrum of additional opportunities opens.

Spectrum of Fontan-associated liver disease assessed by MRI and US in young adolescents.

PURPOSE: Patients with Fontan circulation are at risk of developing hepatic fibrosis/cirrhosis. The mechanisms and disease development are unclear and early secondary liver cancer is a concern. This study will describe hepatic imaging findings in a national cohort of adolescents with Fontan circulation. METHODS: The patients prospectively underwent abdominal contrast enhanced magnetic resonance imaging (MRI) including diffusion-weighted imaging. Images were assessed for criteria of fibrosis/cirrhosis including characterization of hepatic nodules. These nodules were in addition, assessed by ultrasonography (US). Nodules ≥ 1 cm were investigated and monitored to evaluate malignant transformation. Clinical and hepatic serological data were recorded. RESULTS: Forty-six patients, median age of 16.5 years (15.4-17.9 years) were enrolled. All patients underwent US examination and MRI was performed in 35/46 patients. On MRI, 60% had hepatomegaly and 37% had signs of fibrosis/cirrhosis. Seven patients had together 13 nodules ≥ 1 cm in diameter. Only 4/13 (17%) where seen on US. Nodules had variable MRI signal characteristics including hepatobiliary contrast enhancement and two nodules revealed portal venous phase 'wash-out' on the first examination. No further imaging signs of malignancy were revealed during the follow-up period of median 24.4 (7-42) months. CONCLUSION: The majority of adolescents with Fontan circulation had imaging findings of fibrosis/cirrhosis of varying severity. US had low detection rate of hepatic nodules compared to MRI. The imaging work-up before transition to adult cardiology care did not reveal findings suggestive of malignancy. However, the high prevalence of Fontan-associated liver disease calls for surveillance strategies even in childhood.

Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation.

PURPOSE: Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation. METHODS: A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7-12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses. RESULTS: During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger. CONCLUSION: Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.

Early Signs of Sinoatrial Reinnervation in the Transplanted Heart.

BACKGROUND: Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. METHODS: Fifty HTx recipients were assessed at 2.5, 6, and 12 mo after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were performed at supine rest, 0.2 Hz controlled breathing, 60° head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. RESULTS: In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased, while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 mo. CONCLUSIONS: Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 mo after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 mo. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.

Hepatic magnetic resonance T1-mapping and extracellular volume fraction compared to shear-wave elastography in pediatric Fontan-associated liver disease.

BACKGROUND: Children with Fontan circulation are at risk of developing hepatic fibrosis/cirrhosis. Reliable noninvasive monitoring techniques are lacking or under development. OBJECTIVE: To investigate surrogate indicators of hepatic fibrosis in adolescents with Fontan circulation by evaluating hepatic magnetic resonance (MR) T1 mapping and extracellular volume fraction measurements compared to US shear-wave elastography. MATERIALS AND METHODS: We analyzed hepatic native T1 times and extracellular volume fractions with modified Look-Locker inversion recovery. Liver stiffness was analyzed with shear-wave elastography. We compared results between 45 pediatric patients ages 16.7±0.6 years with Fontan circulation and 15 healthy controls ages 19.2±1.2 years. Measurements were correlated to clinical and hemodynamic data from cardiac catheterization. RESULTS: MR mapping was successful in 35/45 patients, revealing higher hepatic T1 times (774±44 ms) than in controls (632±52 ms; P<0.001) and higher extracellular volume fractions (47.4±5.0%) than in controls (34.6±3.8%; P<0.001). Liver stiffness was 1.91±0.13 m/s in patients vs. 1.20±0.10 m/s in controls (P<0.001). Native T1 times correlated with central venous pressures (r=0.5, P=0.007). Native T1 was not correlated with elastography in patients (r=0.2, P=0.1) or controls (r = -0.3, P=0.3). Extracellular volume fraction was correlated with elastography in patients (r=0.5, P=0.005) but not in controls (r=0.2, P=0.6). CONCLUSION: Increased hepatic MR relaxometry and shear-wave elastography values in adolescents with Fontan circulation suggested the presence of hepatic fibrosis or congestion. Central venous pressure was related to T1 times. Changes were detected differently with MR relaxometry and elastography; thus, these techniques should not be used interchangeably in monitoring hepatic fibrosis.

Progressive loss of bone mass in children with Fontan circulation.

OBJECTIVE: We investigated bone mineral density (BMD) at different ages after the Fontan completion, and we evaluated the relationship between BMD, vitamin D levels, and pertinent patient variables. METHODS: A cross-sectional sample of 64 patients was examined with dual-energy X-ray absorptiometry (DXA) scans to determine BMD. Of these patients, 24 were also examined with BoneXpert software to determine bone mass density (BMX), expressed as the bone health index (BHI). Blood samples from all patients were analyzed. Patients were divided into three different age groups; A: 4-9 years old (n = 22), B: 10-15 years old (n = 21), and C: 16-18 years old (n = 21). RESULTS: Overall, BMD z scores were (mean ± SD): -1.0 ± 1.3 for the lumbar spine and -0.2 ± 1.2 for the total body. Groups B and C had significantly lower z score values compared to group A. Of patients in group C, 35% had z score values ≤-2 SD of the mean of the healthy population. There was no difference related to systemic ventricular anatomy (left or right); however, patients with lateral tunnels had lower BMD than patients with extra cardiac conduits. Overall, the BHI z score was (mean ± SD): -1.2 ± 0.9, but low BMX did not correlate with low BMD. The 25-hydroxy vitamin D level was 58 ± 30 nmol/L. Vitamin D levels decreased with age: in group C, 33.3% of patients exhibited vitamin D deficiencies. Vitamin D levels were not correlated with bone mineral densities. CONCLUSION: BMD levels decreased with age in patients with Fontan circulation. Different bone components were involved. Vitamin D levels also decreased with age, but they were not consistently associated with bone mineral densities. The single factor most predictive of low BMD was a lateral tunnel Fontan, compared to an extra cardiac Fontan.

Autonomic cardiovascular control changes in recent heart transplant recipients lead to physiological limitations in response to orthostatic challenge and isometric exercise.

PURPOSE: Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR). METHODS: A total of 50 HTxRs were investigated 7-12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted. RESULTS: At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands. CONCLUSION: HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

Right ventricular pressure response to exercise in adults with isolated ventricular septal defect closed in early childhood.

We previously demonstrated an abnormally high right ventricular systolic pressure response to exercise in 50% of adolescents operated on for isolated ventricular septal defect. The present study investigated the prevalence of abnormal right ventricular systolic pressure response in 20 adult (age 30-45 years) patients who underwent surgery for early ventricular septal defect closure and its association with impaired ventricular function, pulmonary function, or exercise capacity. The patients underwent cardiopulmonary tests, including exercise stress echocardiography. Five of 19 patients (26%) presented an abnormal right ventricular systolic pressure response to exercise ⩾ 52 mmHg. Right ventricular systolic function was mixed, with normal tricuspid annular plane systolic excursion and fractional area change, but abnormal tricuspid annular systolic motion velocity (median 6.7 cm/second) and isovolumetric acceleration (median 0.8 m/second2). Left ventricular systolic and diastolic function was normal at rest as measured by the peak systolic velocity of the lateral wall and isovolumic acceleration, early diastolic velocity, and ratio of early diastolic flow to tissue velocity, except for ejection fraction (median 53%). The myocardial performance index was abnormal for both the left and right ventricle. Peak oxygen uptake was normal (mean z score -0.4, 95% CI -2.8-0.3). There was no association between an abnormal right ventricular systolic pressure response during exercise and right or left ventricular function, pulmonary function, or exercise capacity. Abnormal right ventricular pressure response is not more frequent in adult patients compared with adolescents. This does not support the theory of progressive pulmonary vascular disease following closure of left-to-right shunts.

Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI.

This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision-making.

Achievements in congenital heart defect surgery: a prospective, 40-year study of 7038 patients.

BACKGROUND: This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades. METHODS AND RESULTS: From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (P<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (P=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (P=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (P=0.0001). CONCLUSIONS: Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality.

Hyperoxic resuscitation after hypoxia-ischemia induces cerebral inflammation that is attenuated by tempol in a reporter mouse model with very young mice.

BACKGROUND: Oxygen supplementation is still part of international resuscitation protocols for premature children. Mechanisms for tissue damage by hypoxia/ischemia in the extreme premature involve inflammation. AIM AND METHOD: To study cerebral inflammation after hypoxia/ischemia and oxygen treatment in the premature, we measured NF-κB activity in 5-day-old transgenic reporter mice in response to experimental hypoxia/ischemia. results were correlated to cerebral histological evaluation and plasma cytokine levels. A treatment strategy with the antioxidant tempol was tested. RESULTS: One day after hypoxia/ischemia NF-κB activation was increased compared to controls [mean difference: 10.6±4.6% (P=0.03)]. Exposure to 100% oxygen after hypoxia/ischemia further increased NF-κB activation compared to hypoxia/ischemia alone [mean difference: 15.0±5.5% (P=0.01)]. Histological changes in the brain were positively correlated with NF-κB activity (P<0.001), but we found no significant difference in tissue damage between resuscitation with air and resuscitation with pure oxygen. Administration of tempol reduced NF-κB activation [mean difference: 14.6±5.0% (P=0.01)] and the plasma level of cytokines; however, the histological damage score was not affected. CONCLUSION: Cerebral inflammatory response after hypoxia/ischemia in a mouse model with immature brain development corresponding to human prematurity prior to 32 weeks' gestation was influenced by administration of oxygen. Tempol treatment attenuated inflammation but did not reduce the extent of histological cerebral damage.

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial.

BACKGROUND: This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects. FINDINGS: Five adolescent CFS patients (14-19 years old) received 50 µg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) µg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) µg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered. CONCLUSION: Clonidine 50 µg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

Mechanisms of exercise-induced pulmonary hypertension in patients with cardiac septal defects.

The objective of this study was to investigate mechanisms of exercise-induced pulmonary hypertension in patients with congenital cardiac septal defects. This was a randomized, placebo controlled, crossover drug trial in a single national pediatric cardiology centre that performs congenital cardiac defect surgery. There were 14 patients with cardiac septal defects and known exercise-induced pulmonary hypertension. The intervention consisted of 50 mg oral sildenafil versus placebo. Measurements included supine bicycle exercise echocardiography and oxygen uptake. The outcome measure was right-ventricular systolic pressure as estimated by Doppler tracings of tricuspid regurgitant jet as well as systolic and diastolic longitudinal myocardial velocities by color tissue Doppler echocardiography. Sildenafil did not change exercise right-ventricular systolic pressure during exercise; however, decreased systemic systolic pressure was seen. Enhanced biventricular longitudinal function with sildenafil compared with placebo was indicated by greater tissue Doppler velocities and displacement measurements during exercise. Finally, a less steep increase of right-ventricular pressure during exercise was associated with greater left-ventricular diastolic myocardial tissue Doppler velocity. Exercise-induced pulmonary hypertension in cardiac septal defects does not seem to have a pulmonary vasoconstrictive component, but it may be related to left-ventricular filling pressure. Furthermore, sildenafil improved biventricular systolic performance in this patient group, possibly related to decreased systemic afterload.

Adolescent chronic fatigue syndrome; a follow-up study displays concurrent improvement of circulatory abnormalities and clinical symptoms.

BACKGROUND: The pathophysiology of chronic fatigue syndrome (CFS) in adolescents is unknown, and the clinical course and prognosis is still questioned. Recent research indicates that abnormalities of autonomic cardiovascular control may play an important role. The aim of this research project was to perform a follow-up study of adolescents with chronic fatigue syndrome, focusing on clinical symptoms and autonomic cardiovascular control. METHODS: 47 adolescents (12-18 years old) with CFS were recruited from the outpatient clinic at the Department of Pediatrics, Oslo University Hospital. In a primary visit and a follow-up visit (3-17 months later), we evaluated: a) a wide range of complaints and symptoms and b) cardiovascular variables at baseline and during a 20° head-up tilt-test (HUT). RESULTS: At the second visit, patients reported significant improvement regarding functional impairments, fatigue severity, muscular pain, concentration problems, post-exertional malaise and the problem of non-relieving rest. Also, at the second visit, baseline heart rate (HR), blood pressure, total peripheral resistance index (TPRI) and LF/HF (low-frequency:high-frequency heart rate variability ratio, an index of sinus node sympathovagal balance derived from spectral analyses of heart rate) were significant lower, and the increases in HR, mean blood pressure (MBP), diastolic blood pressure (DBP) and TPRI during tilt were significantly less pronounced as compared to the first visit. There was a significant correlation between changes in autonomic symptom score, fatigue severity score and functional impairment score from the first to the second visit. CONCLUSIONS: The majority of adolescents with CFS experienced an improvement over time in functional impairment, self-reported fatigue and additional symptoms, and a concurrent improvement of autonomic cardiovascular control. A possible connection between clinical symptoms and abnormal autonomic control in CFS might represent a focus for further research.

Chemokines regulate small leucine-rich proteoglycans in the extracellular matrix of the pressure-overloaded right ventricle.

Chemokines have been suggested to play a role during development of left ventricular failure, but little is known about their role during right ventricular (RV) remodeling and dysfunction. We have previously shown that the chemokine (C-X-C motif) ligand 13 (CXCL13) regulates small leucine-rich proteoglycans (SLRPs). We hypothesized that chemokines are upregulated in the pressure-overloaded RV, and that they regulate SLRPs. Mice with RV pressure overload following pulmonary banding (PB) had a significant increase in RV weight and an increase in liver weight after 1 wk. Microarray analysis (Affymetrix) of RV tissue from mice with PB revealed that CXCL10, CXCL6, chemokine (C-X3-C motif) ligand 1 (CX3CL1), chemokine (C-C motif) ligand 5 (CCL5), CXCL16, and CCL2 were the most upregulated chemokines. Stimulation of cardiac fibroblasts with these same chemokines showed that CXCL16 increased the expression of the four SLRPs: decorin, lumican, biglycan, and fibromodulin. CCL5 increased the same SLRPs, except decorin, whereas CX3CL1 increased the expression of decorin and lumican. CXCL16, CX3CL1, and CCL5 were also shown to increase the levels of glycosylated decorin and lumican in the medium after stimulation of fibroblasts. In the pressure-overloaded RV tissue, Western blotting revealed an increase in the total protein level of lumican and a glycosylated form of decorin with a higher molecular weight compared with control mice. Both mice with PB and patients with pulmonary stenosis had significantly increased circulating levels of CXCL16 compared with healthy controls measured by enzyme immunoassay. In conclusion, we have found that chemokines are upregulated in the pressure-overloaded RV and that CXCL16, CX3CL1, and CCL5 regulate expression and posttranslational modifications of SLRPs in cardiac fibroblasts. In the pressure-overloaded RV, protein levels of lumican were increased, and a glycosylated form of decorin with a high molecular weight appeared.