Objectively measured physical activity levels of young children with congenital heart disease.

UNLABELLED: Physical activity tends to be lower in school-age children with congenital heart disease than in healthy controls. To the best of our knowledge, objectively measured physical activity levels of preschool-age children with congenital heart disease have not been studied. METHODS: A total of 10 children with either coarctation of the aorta (n=6; age 3.8±0.9) or tetralogy of Fallot (n=4, age 4.3±0.9) were recruited from the cardiology unit of McMaster Children's Hospital. Height (103.7±8.2 cm) and weight (17.3±2.7 kg) measurements were recorded, and physical activity was determined using accelerometry over 7 consecutive days. Patients were compared with age-, sex-, and season of data acquisition-matched controls. Parents completed a questionnaire regarding the child's physical activity and sedentary behaviours. RESULTS: Patients spent on average 219.4±39.9 minutes engaged in total physical activity per day at the following intensities: light, 147.5±22.3; moderate, 44.0±11.8; moderate-to-vigorous, 71.9±22.6; and vigorous, 27.9±11.7. No significant differences were observed between patients and controls for total physical activity (p=0.80) or any of the intensities (p=0.71, 0.46, 0.43, and 0.45, respectively). Only 40% of patients and controls met the new Canadian Physical Activity Guidelines for the Early Years of at least 180 minutes of physical activity at any intensity every day. Of the patients' parents, 90% believed that their child was as active, if not more active, than his/her siblings, and 80% of parents reported their child spending 1-3 hours in screen time activities daily. CONCLUSION: Children aged 3-5 years old with congenital heart disease have comparable physical activity levels to age-, sex-, and season-matched controls, and many do not meet Canadian Physical Activity Guidelines.

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how.

BACKGROUND: Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations--such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers--on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials. DISCUSSION: In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials. SUMMARY: When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

Educational paper: decreasing the burden of cardiovascular disease in childhood cancer survivors: an update for the pediatrician.

The cardiovascular impact of cancer therapies on the heart is one of the major concerns in the long-term follow-up of childhood cancer survivors (CCSs). Long-term cardiovascular effects include the development of left ventricular dysfunction resulting in congestive heart failure and ischemic heart disease, as well as valvular and pericardial disease. This is mainly ascribed to the cardiotoxic side effects of chemotherapeutic agents (especially anthracyclines) and radiotherapy, but other factors such as radiation and inflammation play a role in the effect of childhood cancer on the cardiovascular health. The most concerning effect is the high incidence of symptomatic heart failure in CCS patients treated with anthracyclines. More than 50 % of CCSs treated with anthracyclines develop asymptomatic left ventricular dysfunction after cancer therapy, with approximately 5 % developing clinical signs of heart failure during long-term follow-up. Once CCS patients develop congestive heart failure, prognosis is poor and is not influenced by current medical treatment strategies. To reduce the long-term burden of cardiovascular disease in pediatric cancer patients, a diversified approach will be necessary. In the acute phase, prevention of cardiac damage through the use of cardioprotective agents (e.g., dexrazoxane) or by administering less cardiotoxic chemotherapeutic agents is to be considered. A recent randomized trial suggested that the use of dexrazoxane reduced cardiac toxicity without affecting cancer outcomes. Especially patients requiring high doses of chemotherapeutic agents could benefit from this approach. Recent data suggest that genetic testing might identify patients at higher risk for cardiotoxicity. This seems mainly related to genes involved in drug metabolism. This would allow personalized approach adjusting chemotherapy based on cardiovascular risk profiling. This could be combined with newer monitoring strategies in the acute phase using newer echocardiographic techniques and biomarker screening to identify patients with early damage to the myocardium. For the long-term CCS cohort, early detection and treatment of early dysfunction prior to the development of congestive heart failure could potentially improve long-term outcomes. Promoting healthy lifestyles and controlling additional cardiovascular risk factors (e.g., obesity, diabetes, arterial hypertension) is an important task for every physician involved in the care of this growing cohort.

Inactive Lifestyles Among Young Children With Innocent Murmurs or Congenital Heart Disease, Regardless of Disease Severity or Treatment.

BACKGROUND: Sedentary lifestyle morbidities are common among children with congenital heart disease (CHD). Understanding the physical activity trajectory from early childhood could enhance timing and effectiveness of interventions. METHODS: We recruited 154 children (56% male) at 12 to 47 months of age for this prospective, longitudinal, observational study. Physical activity and sedentary behaviour (7-day accelerometry) and motor skill (Peabody Developmental Motor Scales-2) were assessed every 8 months until 5 years of age and then annually. Mixed-effect repeated measures regression models described outcome trajectories across study assessments. RESULTS: Children had innocent heart murmurs (n = 28), CHD with insignificant hemodynamics not requiring treatment (n = 47), CHD treated by catheterization or surgery without cardiopulmonary bypass (n = 31), or CHD treated surgically with bypass (n = 48). Motor skill was age appropriate (Peabody 49.0 ± 8.4), but participants had lower physical activity (143 ± 41 minutes per day) and higher sedentary time (598 ± 89 minutes per day) than healthy peers, starting at 18 months of age. Movement behaviours were not related to treatment group (P > 0.10), and physical activity was below the recommended 180 minutes per day. Over time, physical activity, sedentary time, and motor skills were primarily related to the baseline measure of each outcome (P < 0.001). CONCLUSIONS: Children with simple or complex CHD or innocent heart murmurs have increased risk for sedentary lifestyles. Their physical activity and sedentary behaviours are established before 2 years of age, persist until school age, and are unrelated to motor skills. These results emphasize the need for interventions targeting the youngest children seen in cardiac clinics, regardless of diagnoses of CHD or innocent murmur.

Repeated systematic surveillance of Kawasaki disease in Ontario from 1995 to 2006.

BACKGROUND: Rising incidences of Kawasaki disease (KD) have been reported worldwide. Reported herein are the results of 4 triennial KD surveillances conducted in Ontario. METHODS: Between 1995 and 2006 all hospitals in Ontario were asked on 4 occasions to identify all patients with discharge diagnoses of KD and report incident cases. RESULTS: The latest surveillance identified 697 new KD patients (100% response rate) for a total of 2378 KD patients through all 4 surveillances. Yearly incidence was 26.2/100,000 for <5 years old, 6.7/100,000 for 5-9 years old and 0.9/100,000 for 10-14 years old. KD incidence significantly increased from 1995 to 2006, although the increase seemed to plateau between the 3rd and 4th surveillance. There was an increase in the proportion of patients diagnosed with incomplete KD and a significant reduction in the rate of coronary artery abnormalities, possibly due to better disease recognition and treatment. Hospitals reporting <20 cases per surveillance were found to be more likely to report cases with incomplete KD. These patients were also less likely to be treated with i.v. immunoglobulin and aspirin but were more likely to be treated with antibiotics, suggesting uncertainties regarding diagnosis and management of KD patients in those centers. CONCLUSIONS: The incidence of KD in Ontario is possibly one of the highest outside of Asia and has been rising since 1995. Although the most recent surveillance demonstrated improved cardiac outcomes, treatment delays or absence thereof continue to be a problem. Effective diagnosis and prompt treatment remain critical aspects of KD management.

Outcomes after corrective surgery for congenital dextro-transposition of the arteries using the arterial switch technique: a scoping systematic review.

BACKGROUND: Dextro-transposition of the great arteries (D-TGA) is the most frequent cyanotic congenital heart pathology in neonates. Surgical correction of this condition is possible using the arterial switch operation (ASO) which was first performed by Jatene in 1975. OBJECTIVES: The aim of this study was to summarise the evidence on short- (less than 1 year), medium- (1-20 years), and long-term (more than 20 years) outcomes of children with D-TGA treated with the ASO. The primary outcome was survival. Secondary outcomes were freedom from cardiac reoperations, occurrence of aortic insufficiency, pulmonary stenosis, coronary artery anomalies, neuropsychological development problems and quality of life. METHODS: We searched MEDLINE, EMBASE, CINAHL, LILACS, and reference lists of included articles for studies reporting outcomes after ASO for D-TGA. Screening, data extraction and risk of bias assessment were done independently by two reviewers. We pooled data using a random-effects meta-analysis of proportions and, where not possible, outcomes were synthesized narratively. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the certainty of the evidence for each outcome. MAIN RESULTS: Following ASO for TGA, short-term survival was 92.0% (95% CI 91.0-93.0%; I2 = 85.8%, 151 studies, 30,186 participants; moderate certainty evidence). Medium-term survival was 90.0% (95% CI 89.0-91.0%; I2 = 84.3%, 133 studies; 23,686 participants, moderate certainty evidence), while long-term survival was 87.0% (95% CI 80.0-92.0 %; I2 = 84.5%, 4 studies, 933 participants, very low certainty evidence). Evaluation of the different secondary outcomes also showed satisfactory results in the short, medium and long term. Subgroup analysis suggests slightly higher survival following ASO for TGA in the second surgical era (1998 to 2018) than in the first surgical era (1975 to 1997) in the short and medium term [93.0% (95% CI 92.0-94.0) vs 90.0% (95% CI 89.0-92.0) and 93.0% (95% CI 91.0-94.0) vs 88.0% (87.0-90.0%) respectively] but not in the long term [81.0% (95% CI 76.0-86.0%) vs 89.0% (80.0-95.0%)]. CONCLUSIONS: Pooled data from many sources suggests that the ASO for D-TGA leads to high rates of survival in the short, medium, and long term.

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.

BACKGROUND: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS: Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10-15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS: Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778).

Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer.

BACKGROUND: Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain. METHODS: CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS). RESULTS: Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS (Z score, <-2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs. CONCLUSIONS: Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.

Epidemiology of Kawasaki Disease in Canada 2004 to 2014: Comparison of Surveillance Using Administrative Data vs Periodic Medical Record Review.

BACKGROUND: We have previously documented an increase in the incidence of Kawasaki disease (KD) in Ontario followed by a stabilization from 1995 to 2006. We sought to validate the estimation of incidence of KD using administrative data and to describe the epidemiology of KD across Canada from 2004 to 2014. METHODS: We queried the Canadian Hospital Discharge Database for hospital admissions associated with a discharge diagnosis of KD. The data set was manually curated and estimates of incidence were compared with those obtained from the retrospective triennial surveillances of KD performed in 2007 and 2010. RESULTS: The average number of cases per year identified through administrative data was 245 ± 45 vs 229 ± 33 from retrospective surveillance. This overestimation, representing 7 ± 6%, is similar to the historical percentage of patients originally diagnosed with KD in whom the diagnosis is subsequently excluded. The annual incidence of KD in Canada was 19.6, 6.4, and 1.3 cases per 100,000 children younger than 5 years, 5-9 years, and 10-14 years old, respectively, with important regional and seasonal differences. The incidence remained stable over the study period in the youngest age group but increased in both older age categories. Coronary artery aneurysms affected 3.5% of all patients, and 0.8% experienced associated major cardiac complications. CONCLUSIONS: Reliance on administrative data to determine incidence of KD is feasible and accurate with manual curation of the data. The incidence of KD in Canada seems to have plateaued for younger children. Differences in annual incidence observed between provinces remain to be explained, and might reflect genetic or environmental differences.

Recruitment feasibility to a cohort study of endocrine and metabolic health among survivors of childhood brain tumours: a report from the Canadian study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE).

OBJECTIVES: The aim of this study was to test the feasibility of recruitment and performance of study procedures of the Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE) study, which was designed to assess the determinants of endocrine and metabolic health in survivors of childhood brain tumours. SETTING: A single paediatric tertiary care centre in Hamilton, Ontario, Canada. PARTICIPANTS: We included boys and girls, aged 5 years and older, who were lean (body mass index (BMI) below 85th centile for age and gender) or overweight/obese (BMI 85th centile or above for age and gender). We excluded children on steroids or immunosuppressant therapy, smokers and those who had an active infection for the 2 weeks prior to participation. OUTCOMES: Feasibility targets included recruitment rate of at least 50%, the consenting of 80% of participants to provide biological samples, 90% questionnaire completion rate and the ability to process biological samples from at least 80% of participants. RESULTS: We approached 210 potential participants, and of the 112 (53%) who agreed to participate, 30 (26.8%) completed the study visit over 7 months. All participants agreed to fast, provide biological samples and complete the questionnaires. Sample collection was successful in 97% (29/30) of participants and laboratory procedures were feasible in 100% of collected samples. We also tested resources required for the conduct of the full study including personnel, space, laboratory equipment and procedures and determined that they are all feasible. CONCLUSIONS: Recruitment and consenting of patients for the CanDECIDE study may be feasible. However, we are considering prolonging recruitment duration and collaboration with other centres to meet recruitment targets due to lower than expected recruitment rate. Completion of questionnaires and implementation of sample processing protocols are feasible.

Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE study): a cohort study protocol examining the mechanisms of obesity in survivors of childhood brain tumours.

BACKGROUND: Childhood obesity has reached epidemic proportions and is impacting children's health globally. In adults, obesity is associated with chronic low-grade inflammation that leads to insulin resistance, which is one of the important mechanisms through which dysregulation of metabolism occurs. There is limited information available about the contribution of inflammation to metabolic health in obese children, and how individual and lifestyle factors impact this risk. One of the paediatric groups at risk of higher rates of obesity includes the survivors of childhood brain tumours. The aim of this study was to evaluate the mechanisms that contribute to inflammation in obese survivors of childhood brain tumours. METHODS AND ANALYSIS: This is a prospective cohort study. We will recruit lean and obese survivors of childhood brain tumours, and a control group composed of lean and obese children with no history of tumours. We will measure circulating and urinary cytokine levels and cytokine gene expression in monocytes. In addition, the methylation patterns of cytokine genes and that of toll-like receptor genes will be evaluated. These will be correlated with individual and lifestyle factors including age, sex, ethnicity, puberty, body mass index, fasting lipid levels, insulin sensitivity, diet, exercise, sleep, stress and built environment. The sample size calculation showed that we need 25 participants per arm ETHICS AND DISSEMINATION: This study has received ethics approval from the institutional review board. Once completed, we will publish this work in peer-reviewed journals and share the findings in presentations and posters in meetings. DISCUSSION: This study will permit the interrogation of inflammation as a contributor to obesity and its complications in obese survivors of childhood brain tumours and compare them with lean survivors and lean and obese controls with no history of tumours, which may help identify therapeutic and preventative interventions to combat the rising tide of obesity.

A systematic scoping review of adherence to reporting guidelines in health care literature.

BACKGROUND: Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies. METHODS: We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines. RESULTS: Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies. CONCLUSION: Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines.

Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines.

Pediatric heart failure (HF) is an important cause of morbidity and mortality in childhood. This article presents guidelines for the recognition, diagnosis, and early medical management of HF in infancy, childhood, and adolescence. The guidelines are intended to assist practitioners in office-based or emergency room practice, who encounter children with undiagnosed heart disease and symptoms of possible HF, rather than those who have already received surgical palliation. The guidelines have been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and are accompanied by practical Recommendations for their application in the clinical setting, supplemented by online material. This work does not include Recommendations for advanced management involving ventricular assist devices, or other device therapies.

Vascular and autonomic function in preschool-aged children with congenital heart disease.

OBJECTIVE: To compare indices of vascular health and heart rate variability in preschool-aged children with repaired congenital heart disease (CHD) including tetralogy of Fallot (n = 6) and coarctation of the aorta (n = 6). DESIGN: A cross-sectional study design was used. All measures were noninvasive and collected over a single testing session under the supervision of a parent/guardian. SETTING: Data collection took place in a quiet, temperature-controlled room (23°± 1°C) with the participant in a supine position. PATIENTS: Twelve (six females, six males) preschool-aged children with repaired CHD (CHD: 4 ± 1 years) and 12 age- and gender-matched healthy controls (CON: 5 ± 1 years) participated in the study. OUTCOME MEASURES: Supine, resting measures of heart rate variability (time, frequency, and nonlinear domains), whole-body pulse wave velocity (ventricular depolarization to dorsalis pedis artery), brachial blood pressures, and carotid artery distensibility, lumen diameter, intima-media thickness, and wall/lumen ratio were collected in both groups. RESULTS: The groups were similar in age, height, and weight; however, CON had significantly higher body mass index values (CON: 16.9 ± 2.2, CHD: 15.1 ± 1.0, P < .05) and body mass index percentiles (CON: 69 ± 27%tile, CHD: 36 ± 24%tile, P < .01) compared to CHD. No group differences were found for resting brachial blood pressures, whole-body pulse wave velocity, heart rate variability, and carotid artery distensibility, lumen diameter, and intima-media thickness (P > .05). Carotid artery pulse pressures (CHD: 38 ± 6 mm Hg, CON: 31 ± 6 mm Hg, P < .05) and wall/lumen ratios (CHD: 0.091 ± 0.007, CON: 0.085 ± 0.006, P < .01) were significantly higher in the CHD group. CONCLUSIONS: These results may indicate that preschool-aged children with repaired CHD display early signs of vascular remodeling, but not autonomic or vascular dysfunction. The effects of larger wall/lumen ratios on cardiovascular disease risk require further investigation.

Parental anxiety associated with Kawasaki disease in previously healthy children.

OBJECTIVE: The objective of this study was to explore the lived experience of parents of children diagnosed with Kawasaki disease (KD) and to identify factors associated with increased levels of parental anxiety. STUDY DESIGN: Three focus groups were conducted including 25 parents of 17 patients with KD, seven (41%) of whom had coronary artery complications. A conceptual model was developed to depict parental experiences and illustrate the key issues related to heightened anxiety. RESULTS: Themes identified included anxiety related to the child's sudden illness and delay in obtaining a correct diagnosis because of the lack of health care providers' awareness and knowledge regarding KD. Parents were frustrated by the lack of information available in lay language and the limited scientific knowledge regarding the long-term consequences of the disease. Parents also reported positive transformations and different perspective toward challenges in life. However, the parents of children with coronary artery complications expressed persistent anxiety even years after the acute phase of the illness due to the uncertainty of the long-term prognosis. CONCLUSIONS: There remains a critical need for richly textured research data on the perspective and experience of families of children with KD.

Central serotoninergic response to orthostatic challenge in patients with neurocardiogenic syncope.

AIMS: To determine whether central serotoninergic system activity is impaired by orthostatic challenge in patients with neurocardiogenic syncope (NCS). METHODS AND RESULTS: Thirty-five [mean age: 24 (SD): 6 years] patients with a clinical history of NCS and positive head-up tilt test and 35 age-matched healthy volunteers (CON = 25+/-5 years) with negative response were studied. Overnight dexamethasone suppression test (DST) (1.5 mg given at 11 p.m.) was performed to assess the sensitivity of the hypothalamic-pituitary-adrenal axis by measuring next day cortisol (microg/dL) at 8 a.m. and 4 p.m. Cardiac autonomic function, cortisol, and prolactin (ng/dL) were also determined at baseline supine (BAS) and after 5, 10, and 15 min of orthostatic stress (OS) at 60 degrees . No significant differences were observed in cortisol plasma levels after the DST: CON = 0.6+/-0.6 microg/dL vs. NCS = 0.6+/-0.5; P = 0.7. Cardiac autonomic function, cortisol, and prolactin responses were similar in both study groups (CON vs. NCS; P > 0.05) during BAS: cortisol = 8.6+/-4 vs.8.7+/-4 microg/dL and prolactin = 16.8+/-9 vs. 16.8+/-9 ng/dL; OS-5: cortisol = 8.7+/-5 vs. 8.5+/-4 microg/dL and prolactin = 16.9+/-9 vs. 15.8+/-9 ng/dL; OS-10: cortisol = 8.5+/-5 vs. 8.1+/-3 microg/dL; prolactin = 16.2+/-9 vs. 15.8+/-9 ng/dL, and OS-15: cortisol = 9.0+/-5 vs. 8.4+/-4 microg/dL; prolactin = 17.1+/-9 vs. 15.5+/-9 ng/dL. CONCLUSION: Central serotoninergic response during orthostatic challenge was not impaired in patients with recurrent NCS. These findings suggest that the activation of the hypothalamic-pituitary-adrenal axis is not altered in patients with recurrent NCS.

Impaired baroreflex gain in patients with inappropriate sinus tachycardia.

INTRODUCTION: The aim of this study was to determine the characteristics of heart rate variability (HRV), blood pressure variability (BPV), and baroreflex gain (BRG) at rest and during orthostatic stress in patients with clinical criteria of inappropriate sinus tachycardia (IST). METHODS AND RESULTS: Beat-to-beat HRV and BPV, measured by time- and frequency-domain methods, and noninvasive BRG, calculated by cross-spectral analysis, were obtained during 10 minutes both at rest and during the stabilization phase (5-15 min) of orthostatic stress at 60 degrees in 8 patients with clinical criteria of IST and 9 healthy volunteers (CON). IST patients had a higher resting mean heart rate (78.8 +/- 5.3 vs 58.5 +/- 4.2 beats/min, P=0.01) and mean blood pressure (90.4 +/- 2.4 vs 72.0 +/- 4.2 mmHg; P=0.002). RMSSD, pNN50m, and BRG were significantly reduced in IST patients at rest. BRG during orthostatic stress (7.2 +/- 0.8 vs 20.3 (2.4 ms/mmHg, P <0.01) was significantly reduced in IST patients. Delta BRG (-16.9%+/- 11 vs -50.1%+/- 5, P=0.02) was markedly blunted during orthostatic stress in IST patients. CONCLUSION: BRG was markedly impaired both at rest and during orthostatic stress in IST patients. This alteration may be responsible for the higher resting heart rate and mean blood pressures seen at rest and may facilitate tachycardia during orthostatic stress. A primary alteration in sinus node automaticity coupled with impaired BRG determines heart rate response to orthostatic stress in patients with IST.