Greater Arterial Stiffness in Children with or without Second-generation Antipsychotic Treatment for Mental Health Disorders: Rigidité Artérielle Plus Importante Chez Les Enfants Avec ou Sans Traitement Par Antipsychotiques de la Deuxième Génération Pour des Troubles de Santé Mentale.

OBJECTIVE: Second-generation antipsychotics (SGAs) are used for a variety of mental disorders and are associated with cardiometabolic side effects in children. The objective of this study was to assess the cardiovascular health of children with mental disorders that are SGA-treated or SGA-naive. METHODS: SGA-treated (n = 47) or SGA-naive (n = 37) children (aged 6 to 18 years) with mental disorders and control children (n = 83, no mental disorder) underwent assessment for cardiac function and morphology by echocardiography, aortic pulse wave velocity (PWV), and carotid intima-media thickness (cIMT). Body mass index (BMI) z-scores, waist circumference z-scores, systolic and diastolic blood pressure (BP) percentiles for height and sex, and fasting plasma glucose, insulin, triglycerides, and cholesterol were also assessed. Differences between SGA-treated, SGA-naive, and control children were assessed by linear and log-linear regression models. RESULTS: SGA-treated children had greater BMI z-scores and overweight/obesity (BMI ≥ 85th percentile for age and sex) and hypertension than SGA-naive and control children. The PWV geometric mean was 11.1% higher in SGA-treated (95%CI, 3.95 to 18.77) and 12.9% higher in SGA-naive children (95% CI, 5.60 to 20.59) compared to controls in models adjusted for age, sex, BMI, and systolic BP percentile. Left ventricular (LV) end-diastolic dimension/body surface area (BSA), LV end-systolic dimension/BSA, and LV ejection fraction were lower in SGA-treated and SGA-naive children compared to controls in models adjusted for sex and age. CONCLUSIONS: Children with mental disorders have greater arterial stiffness and altered cardiac structure/function than children with no mental health diagnosis. SGA treatment in children is not associated with alterations in cardiovascular structure/function.

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function.

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

Obesity and arterial stiffness in children: systematic review and meta-analysis.

OBJECTIVE: Childhood obesity is associated with risk factors for cardiovascular disease. Arterial stiffness is considered one of the earliest detectable measures of vascular damage. There is controversy in the literature regarding the effects of childhood obesity on arterial stiffness. The objective of this study is to systematically review the literature and to conduct a meta-analysis comparing measures of central arterial stiffness in children and adolescents with obesity to healthy body mass index controls. APPROACH AND RESULTS: Literature searches were conducted using databases (eg, MEDLINE, EMBASE) and citations cross-referenced. Studies assessing central pulse wave velocity or ß-stiffness index were included. A random effects meta-analysis of the standardized mean difference and 95% confidence intervals in arterial stiffness between children with obesity and control children was performed for each arterial stiffness measure. A total of 523 studies were identified. Fifteen case-control studies were included, with 2237 children/adolescents (1281 with obesity, 956 healthy body mass index controls) between 5 and 24 years of age. All studies measuring carotid and aortic ß-stiffness index and 10/12 studies measuring central pulse wave velocity reported greater arterial stiffness in children/adolescents with obesity compared with controls. A random effects meta-analysis was performed revealing a significant effect of obesity on pulse wave velocity (standardized mean difference=0.718; 95% confidence interval=0.291-1.415), carotid ß-stiffness index (0.862; 0.323-1.402), and aortic ß stiffness index (1.017; 0.419-1.615). CONCLUSION: These findings indicate that child/adolescent obesity is associated with greater arterial stiffness. However, further research is needed to address confounders, such as pubertal status, that may affect this relationship in children. In the future, these techniques may be useful in risk stratification and guiding clinical management of obese children to optimize cardiovascular outcomes.

An Echocardiographic Study of Left Ventricular Size and Cardiac Function in Adolescent Females with Anorexia Nervosa.

OBJECTIVE: This retrospective case-control study investigated cardiac dimensions and ventricular function in female adolescents with anorexia nervosa (AN) compared with controls. METHODS: Echocardiographic measurements of left ventricular (LV) dimensions, LV mass index, left atrial size and cardiac index were made. Detailed measures of systolic and diastolic ventricular function were made including tissue Doppler imaging. Patients were stratified by body mass index ≤10th percentile (AN ≤ 10th) and >10th percentile (AN > 10th). RESULTS: Ninety-five AN patients and 58 controls were included. AN and AN ≤ 10th groups had reduced LV dimensions, LV mass index, left atrial size and cardiac index compared with controls. There were no differences between groups in measures of systolic function. Measures of diastolic tissue Doppler imaging were decreased in AN and AN ≤ 10th. No differences in echocardiographic measurements existed between controls and AN > 10th. DISCUSSION: Female adolescents with AN have preserved systolic function and abnormalities of diastolic ventricular function. AN ≤ 10th may be a higher risk group.

Anthracycline induced cardiac toxicity in pediatric Ewing sarcoma: a longitudinal study.

BACKGROUND: Reports on incidence and factors associated with anthracycline cardiotoxicity in patients with Ewing sarcoma vary and few studies evaluate effect over time. Longitudinal trends in cardiac function and prognostic value of % decline in ejection fraction (EF) during therapy have not been previously described in Ewing sarcoma. PROCEDURE: A retrospective review of patients age <17 years, diagnosed with Ewing sarcoma during 1978-2006, treated at British Columbia Children's Hospital with anthracycline chemotherapy was undertaken. Echocardiograms performed pre-treatment, worst function during treatment, on therapy completion; worst function during surveillance and the most recent echocardiogram were reviewed. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events v 3.0 and 4.0. RESULTS: Among 71 eligible patients, median age at diagnosis 11.1 years, median cumulative dose of anthracycline was 365 mg/m2 . There were 397 echocardiograms with 153 (39%) abnormal. There were 21/71 patients with EF < 50%, 11 with EF < 40% and five cardiac deaths including 2/3 patients post-cardiac transplant. The median time to worst cardiac function was 51 months. Post-therapy completion 16/71 patients with progressive decline in cardiac function were noted. No patient with 10-15% decline in EF during therapy developed cardiotoxicity. Younger age (P = 0.004) and low BMI (P = 0.034) as continuous variables with anthracycline administration by IV push (P = 0.03) were risk factors for cardiotoxicity on univariate analysis but not significant within logistic regression models. CONCLUSIONS: The high incidence of cardiotoxicity associated with higher administered anthracycline dose, young age, bolus infusion, and EF decline warrants evaluation in a larger cohort.

Postnatal outcome in patients with fetal tachycardia.

The diagnosis and management of prenatal tachyarrhythmias is well established; however, the postnatal course and outcomes are not. The purpose of our study was to review the natural history of patients with fetal tachycardia, determine the incidence of postnatal arrhythmias, and determine whether there are factors to predict which fetuses will develop postnatal arrhythmias. A retrospective chart review of patients with fetal tachyarrhythmias investigated at British Columbia Children's and Women's Hospitals between 1983 and 2010 was conducted. Sixty-nine mother-fetus pairs were eligible for the study. Fifty-two had fetal supraventricular tachycardia, and 17 had fetal atrial flutter. Conversion to sinus rhythm occurred prenatally in 52 % of patients. Postnatal arrhythmia occurred in two thirds of patients, with 82 % of those cases occurring within the first 48 h of life. Hydrops fetalis, female sex, and lack of conversion to sinus rhythm was predictive of postnatal arrhythmia (P = 0.01, P = 0.01, and P = 0.001, respectively). Conversion to sinus rhythm prenatally did not predict postnatal arrhythmia. Median duration of treatment was 9 months. Two postnatal deaths of unknown etiology occurred. Two thirds of all patients with prenatal tachycardia will develop postnatal arrhythmia. Prenatal factors that predict postnatal arrhythmia include hydrops, sex, and whether or not conversion to sinus rhythm occurred prenatally. The majority of patients with postnatal arrhythmia present within 48 h of life, which has clinical implications for monitoring. Postnatal outcome is generally very good with most patients being weaned off medication in 6-12 months.

Physical activity recommendations for patients with electrophysiologic and structural congenital heart disease: a survey of Canadian health care providers.

Determining safe levels of physical activity for children and adolescents with electrophysiologic and structural congenital heart disease is a challenging clinical problem. The body of evidence for making these recommendations is limited and likely based on expert opinion, medicolegal concerns, and perceived risks of sudden cardiac death (SCD) with activity. The Bethesda Conference has established consensus guidelines for determining the eligibility of athletes with cardiovascular abnormalities for competitive sports and their disqualification from them. However, literature on guidelines for noncompetitive physical activity is not available. A survey was designed to determine practice patterns for patients with electrophysiologic and structural congenital heart disease. Between July 2011 and December 2011, approximately 350 health care providers working with this group of patients were recruited by email or while attending professional meetings. The survey received 81 responses, primarily from pediatric cardiologists (70 %). The findings indicate that the majority of Canadian cardiac care providers surveyed are only partially implementing current recommendations. Areas of variance included physical activity recommendations for hypertrophic cardiomyopathy, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and heart transplantation, among others. The development of comprehensive consensus guidelines for activity recommendations was supported by 96 % of the respondents. The heterogeneity of responses may be attributable to conflicting and poorly evidenced information in the literature, a lack of emphasis on recreational activity, an entrenched tendency toward bed rest in the cardiology community, and a lack of awareness by cardiac care providers regarding the actual risk associated with physical activity in electrophysiologic and structural congenital heart disease. A balanced discussion is required in considering both the significant benefit of physical activity in reducing cardiovascular risk factors and the small possibility of SCD in children and young adults with electrophysiologic and structural congenital heart disease.

Echo-Doppler assessment of the biophysical properties of the aorta in children with chronic kidney disease.

Chronic kidney disease (CKD) is known to cause increased arterial stiffness, which is an important independent risk factor for adverse cardiovascular events. The purpose of this study was to assess the vascular properties of the aorta (AO) in a group of children with CKD using a noninvasive echocardiography (echo)-Doppler method. We studied 24 children with stages 2 through 5 CKD and 48 age-matched controls. Detailed echocardiographic assessment and echo-Doppler pulse wave velocity (PWV) was performed. Indices of arterial stiffness, including characteristic (Zc) and input (Zi) impedances, elastic pressure-strain modulus (Ep), and arterial wall stiffness index, were calculated. CKD patients underwent full nephrology assessment, and an iohexol glomerular filtration rate was performed, which allowed for accurate assignment of the CKD stage. CKD patients had greater median systolic blood pressure (114 vs. 110 mmHg; p < 0.04) and pulse pressure (51 vs. 40 mmHg; p < 0.001) compared with controls. PWV was similar between groups (358 vs. 344 cm s(-1); p = 0.759), whereas Zi (182 vs. 131 dyne s cm(-5); p < 0.001), Zc (146 vs. 138 dyne s cm(-5); p = 0.05), and Ep (280 vs. 230 mmHg; p < 0.02) were significantly greater in CKD than in controls. Although load-dependent measures of arterial stiffness were greater in non-dialysis dependent CKD patients, PWV was not increased compared with controls. This suggests that the increased arterial stiffness may not be permanent in these pediatric patients with kidney disease.

Serial measurements of exercise performance in pediatric heart transplant patients using stress echocardiography.

Heart transplantation is an increasingly acceptable therapeutic option for children with end-stage and complex congenital heart disease. With advances in surgery, immunosuppression, and follow-up care, functional outcomes need to be evaluated. We report the results of serial exercise testing performed using stress echocardiography in a cohort of pediatric HTP. HTP (n = 7) exercised on a semi-recumbent ergometer to volitional fatigue. Echocardiography-Doppler measurements, HR, and blood pressure were taken at rest and during staged exercise. Results were compared with healthy CON (n = 12). HTP did significantly less work during exercise (940 vs. 1218 J/kg, p < 0.03). Their SVI (33 vs. 49 mL/m(2), p < 0.003), CI (5.16 vs. 9.25 L/min/m(2), p < 0.0005), and HR (162 vs. 185 bpm, p < 0.02) were lower at peak exercise. HTP had a lower SF at peak exercise (48% vs. 52%, p < 0.03) and an abnormal relationship between the MVCFc and σPS. During follow-up, hemodynamics and left ventricular function remained relatively constant in HTP. HTP are able to exercise safely; however, their exercise tolerance is reduced, and hemodynamics and contractility are diminished. Over time, their hemodynamics and left ventricular function have remained relatively constant.

Aortic Dimensions, Biophysical Properties, and Plasma Biomarkers in Children and Adults with Marfan or Loeys-Dietz Syndrome.

BACKGROUND: Aortic dilation, stiffening, and dissection are common and potentially lethal complications of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), which involve abnormal transforming growth factor beta (TGF-ß) signalling. The relation of aortic dimensions, stiffness, and biomarker levels is unknown. The objective of this study was to measure aortic dimensions, stiffness, TGF-ß and matrix metalloproteinase (MMP) levels, and endothelial function in patients with MFS, and to compare TGF-ß levels in patients with MFS receiving different therapeutic regimens. METHODS: This was a cohort study of 40 MFS and 4 LDS patients and 87 control participants. Aortic dimension and stiffness indexes, including pulse wave velocity (PWV), were measured using echocardiography and Doppler. Total and free TGF-ß and MMP blood levels were measured using Quantikine (R&D Systems, Inc, Minneapolis, MN) and Quanterix (Billerica, MA) kits. Endothelial function was measured using brachial artery flow-mediated dilation. RESULTS: PWV was increased in patients with MFS. There were increased MMP-2 levels in those with MFS but no increase in free or total TGF-ß or MMP-9 levels compared with control participants. There was no difference in TGF-ß levels between MFS patients receiving no medications, angiotensin receptor blockers, and ß-blockers. PWV correlated most strongly with age. Endothelial function showed premature gradual decline in patients with MFS. CONCLUSIONS: Despite the increased PWV, monitoring aortic stiffness or TGF-ß levels would not be helpful in patients with MFS. TGF-ß levels were not increased and the increased MMP-2 levels suggest consideration of a different therapeutic target.

CONTEXTE: La dilatation, la rigidification et la dissection de l'aorte sont des complications fréquentes et parfois mortelles du syndrome de Marfan (SM) et du syndrome de Loeys-Dietz (SLD), qui sont tous deux dûs à une anomalie de la voie de signalisation du facteur de croissance transformant bêta (TGF-ß). On ne connaît pas la relation entre les dimensions et la rigidité de l'aorte et la présence de biomarqueurs. Notre étude visait à mesurer les dimensions et la rigidité de l'aorte, les taux de TGF-ß et de métalloprotéases matricielles (MMP) et la fonction endothéliale chez des patients atteints du SM, et à les comparer aux taux de TGF-ß observés chez des patients également atteints de SM, mais recevant un autre traitement. MÉTHODOLOGIE: Il s'agissait d'une étude de cohorte menée auprès de 40 patients atteints du SM et de quatre patients atteints du SLD, ainsi que de 87 témoins. Les indices des dimensions et de la rigidité aortiques, y compris la vitesse d'onde de pouls (VOP), ont été mesurés par échocardiographie et par échographie Doppler. Les taux sanguins de TGF-ß et de MMP totaux et libres ont été mesurés à l'aide de trousses Quantikine (R&D Systems, Inc, Minneapolis, MN) et Quanterix (Billerica, MA). La fonction endothéliale a été mesurée par dilatation liée au flux dans l'artère brachiale. RÉSULTATS: La VOP était plus élevée chez les patients atteints du SM. On a aussi observé une hausse des taux de MMP-2 chez les patients atteints de SM, mais aucune augmentation des taux de TGF-ß ou de MMP-9 libres ou totaux comparativement aux témoins. Il n'y avait pas de différence entre les taux de TGF-ß chez les patients atteints de SM ne recevant aucun traitement, ceux qui prenaient un antagoniste des récepteurs de l'angiotensine et ceux qui prenaient un bêtabloquant. La VOP été plus fortement corrélée avec l'âge. La fonction endothéliale a affiché un déclin progressif prématuré chez les patients atteints du SM. CONCLUSIONS: Malgré l'augmentation de la VOP, il ne semble pas utile de surveiller la rigidité aortique ni les taux de TGF-ß en cas de SM. Les taux de TGF-ß n'étaient pas plus élevés chez les patients atteints du SM, et la hausse des taux de MMP-2 indique qu'il conviendrait de choisir une autre cible thérapeutique.

Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.

OBJECTIVE: To assess the biophysical properties of the aorta in children born small for gestational age (SGA) with an echo-Doppler method and to determine associations with known perinatal risk factors. STUDY DESIGN: In this cross-sectional study, 39 SGA and 41 control subjects aged 8 to 13 years were recruited. Perinatal risk factors were recorded. The aortic diameters and pulse wave transit time around the aortic arch were measured with echo-Doppler and the blood pressure recorded. Pulse wave velocity, aortic input impedance (Zi), characteristic impedance (Zc), arterial pressure-strain elastic modulus (Ep), and arterial wall stiffness index (beta-index) were calculated. RESULTS: Pulse wave velocity (374 +/- 46 vs 348 +/- 47 cm/sec, P < .02); Zi (177 +/- 39 vs 142 +/- 27 dynes x sec/cm(5), P < .0001); Zc (185 +/- 29 vs 152 +/- 37 dynes x sec/cm(5), P < .0001); Ep (286 +/- 101 vs 216 +/- 41 mm Hg, P < .0001); and beta-index (2.43 +/- 0.32 vs 2.17 +/- 0.15, P < .0001) were all higher in SGA. We found negative associations between the following: birth weight and Zi, Zc, Ep, and beta-index; as well as body mass index and Zi, Zc. CONCLUSION: This simple echo-Doppler method demonstrated abnormal biophysical properties of the aorta in a cohort of pre-adolescent patients born SGA who remain small in stature and continue to have normal blood pressure.

Primary pulmonary arterial hypertension and autoimmune polyendocrine syndrome in a pediatric patient.

Both primary pulmonary artery hypertension (PPAH) and autoimmune polyendocrine syndrome (APS) are rare disorders in children. We report a boy who was diagnosed with severe PPAH at 12 years of age. He was treated with prostacyclin for 6 years, briefly with adjunct bosentan, and eventually sildenafil was added. Six years later, after his diagnosis of PPAH, he developed APS in the form of hyperthyroidism and type 1 diabetes mellitus. No mutations were identified through genetic testing of bone morphogenetic protein receptor type II and the autoimmune-regulator gene. To our knowledge this is the first description of the combination of these two extremely rare diseases in a child.

Does biventricular pacing improve hemodynamics in children undergoing routine congenital heart surgery?

Biventricular (BiV) pacing or cardiac resynchronization therapy (CRT) is an established therapy for heart failure in adults. In children, cardiac dyssynchrony occurs most commonly following repair of congenital heart disease (CHD) where multisite pacing has been shown to improve both hemodynamics and ventricular function. Determining which patient types would specifically benefit has not yet been established. A prospective, repeated measures design was undertaken to evaluate BiV pacing in a cohort of children undergoing biventricular repair for correction of their CHD. Hemodynamics, arterial blood gas, electrocardiographic (ECG), and echocardiographic data were collected. Pacing protocol was undertaken prior to the patient's extubation with 20 min of conventional right ventricular (RV) or BiV pacing, preceded and followed by 10 min of recovery time. Multivariate statistics were used to analyze the data with p values <0.05 considered significant. Twenty-five (14 female) patients underwent surgery at a median (range) age of 5.2 (0.1-37.4) months with no early mortality. The Risk-adjusted classification for Congenital Heart Surgery (RACHS) scores were 2 in 14 patients, 3 in eight patients, and 4 in three patients. None had pre-existing arrhythmias, dyssynchrony, or required pacing pre-operatively. No patient required implantation of a permanent pacemaker post-operatively. The median cardio-pulmonary bypass time was 96 (55-236) min. RV and BiV pacing did not improve cardiac index from baseline (3.23 vs. 3.42 vs. 3.39 L/min/m2; p > 0.05). The QRS duration was not changed with pacing (100 vs. 80 vs. 80 ms; p > 0.05). On echocardiography, the time-to-peak velocity difference between the septal and posterior walls (synchrony) during pacing was similar to baseline and was also not statistically significant. BiV pacing did not improve cardiac output when compared to intrinsic sinus rhythm or RV pacing in this cohort of patients. Our study has shown that BiV pacing is not indicated in children who have undergone routine BiV congenital heart surgery. Further prospective studies are needed to assess the role of multisite pacing in children with ventricular dyssynchrony such as those with single ventricles, those undergoing reoperation or those with high RACHS scores.

Physical Activity Is Associated With Better Vascular Function in Children and Adolescents With Congenital Heart Disease.

BACKGROUND: Aortic stiffness is an important marker of cardiovascular risk and is elevated in children and adolescents with congenital heart disease (CHD) compared with healthy children; however, in children with CHD, little is known about the interaction between aortic stiffness and physical activity-a key determinant of aortic stiffness. METHODS: For this cross-sectional cohort study, we recruited children and adolescents aged 9-16 years with moderate-to-complex CHD from British Columbia Children's Hospital and travelling partnership clinics across the province of British Columbia and the Yukon territory. Mean daily minutes of moderate-to-vigorous physical activity were objectively assessed using an ActiGraph accelerometer worn over the right hip during waking hours for 7 days. Aortic pulse wave velocity (cm/s) was measured using standard 2-dimensional echocardiography and Doppler ultrasound. RESULTS: Participants (n = 104, 61% male; 85% consent rate) had a mean (standard deviation) age of 12.4 (2.4) years. Daily moderate-to-vigorous physical activity was 46.7 (20.0) minutes/d, with 25% meeting guidelines of ≥ 60 minutes of moderate-to-vigorous physical activity per day. Mean (standard deviation) aortic pulse wave velocity was 490.5 (161.9) cm/s, which was not significantly different between cardiac diagnoses. Higher levels of moderate-to-vigorous physical activity were associated with lower aortic pulse wave velocity (r = -0.226, P = 0.021). CONCLUSION: In children and adolescents with CHD, higher levels of physical activity are associated with better vascular function. Given this association, promoting physical activity should be a high priority in the care of children and adolescents with CHD.

Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome.

Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn1 allele encoding a cysteine substitution in fibrillin-1 (Fbn1(C1039G/+), designated as "Marfan" mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1(+/+) served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of alpha-smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.

Abnormal flow in the posterior descending artery: an echo Doppler clue to the anomalous origin of left anterior descending coronary artery from the pulmonary trunk.

Anomalous origin of the left anterior descending coronary (LAD) from the pulmonary trunk is a rare lesion. We describe a neonate with anomalous origin of the LAD from the pulmonary artery and the circumflex artery arising normally from the left-facing sinus. The finding of a tortuous and dilated posterior descending coronary artery suggested increased intercoronary collateral flow and provided a clue to the identification of the anomaly in an otherwise asymptomatic neonate. Interrogation of the posterior descending coronary artery should be included in the routine echocardiographic examination of children, as unusual flow patterns may help identify aberrant coronary artery connections.

Non-invasive assessment of aortic stiffness and blood pressure in young Turner syndrome patients.

Background Females with Turner syndrome (TS) carry an elevated risk of aortic dissection. The objective of the study was to assess the biophysical properties of the aorta and ambulatory blood pressure (BP) in females with TS and compare these findings to those in healthy female age-matched controls. Methods This was a prospective cohort study including subjects aged 8-25 years. Utilizing two-dimensional (2D) echocardiography and Doppler, proximal aortic dimensions were measured and biophysical properties of the aorta were calculated including pulse wave velocity (PWV), arterial pressure-strain elastic modulus and stiffness index. Resting BP was measured and ambulatory blood pressure monitoring (ABPM) was performed. Results Of 23 TS patients and 46 controls (median age 16.3 years), aortic annulus, sinus of Valsalva and sinotubular (ST) junction diameters, as well as left ventricular (LV) mass, were significantly greater in TS patients compared with controls when scaled for height2.7, but not for body surface area (BSA), although ascending aorta diameter was greater when scaled for both. Median PWV was faster in TS patients compared to controls (451 vs. 360 cm/s) while arterial pressure-strain elastic modulus and stiffness index were similar. Resting BP was abnormal in seven out of 22 patients and ABPM was abnormal in 16 out of 21 patients. Conclusions Young patients with TS had dilated proximal aortas when scaled for height2.7 and stiffer aortas when compared with healthy female age-matched controls. Moreover, resting BP underdiagnosed pre-hypertension and hypertension compared to ABPM. These findings are consistent with the presence of a primary aortopathy in TS.

In vivo characterization of doxycycline-mediated protection of aortic function and structure in a mouse model of Marfan syndrome-associated aortic aneurysm.

Aortic aneurysm is the most life-threatening complication in Marfan syndrome (MFS) patients. Doxycycline, a nonselective matrix metalloproteinases inhibitor, was reported to improve the contractile function and elastic fiber structure and organization in a Marfan mouse aorta using ex vivo small chamber myography. In this study, we assessed the hypothesis that a long-term treatment with doxycycline would reduce aortic root growth, improve aortic wall elasticity as measured by pulse wave velocity, and improve the ultrastructure of elastic fiber in the mouse model of MFS. In our study, longitudinal measurements of aortic root diameters using high-resolution ultrasound imaging display significantly decreased aortic root diameters and lower pulse wave velocity in doxycycline-treated Marfan mice starting at 6 months as compared to their non-treated MFS counterparts. In addition, at the ultrastructural level, our data show that long-term doxycycline treatment corrects the irregularities of elastic fibers within the aortic wall of Marfan mice to the levels similar to those observed in control subjects. Our findings underscore the key role of matrix metalloproteinases during the progression of aortic aneurysm, and provide new insights into the potential therapeutic value of doxycycline in blocking MFS-associated aortic aneurysm.

Echocardiographic Assessment of Ventricular Function During Exercise in Adolescent Female Patients With Anorexia Nervosa.

BACKGROUND: Patients with anorexia nervosa (AN) have altered physiologic responses to exercise. The aim of this study was to investigate exercise capacity and ventricular function during exercise in adolescent patients with AN. METHODS: Sixty-six adolescent female patients with AN and 21 adolescent female control subjects who exercised to volitional fatigue on a semisupine ergometer, using an incremental step protocol of 20 W every 3 min, were retrospectively studied. Heart rate, blood pressure, and echocardiographic Doppler indices were measured at rest and during each stage of exercise. Fractional shortening, rate-corrected mean velocity of circumferential fiber shortening, stress at peak systole, cardiac output, and cardiac index were calculated. Minute ventilation, oxygen consumption, carbon dioxide production, and respiratory exchange ratio were measured using open-circuit spirometry. RESULTS: Patients with AN had significantly lower body mass index (16.7 vs 19.7 kg/m2, P < .001), total work (1,126 vs 1,914 J/kg, P < .001), and test duration (13.8 vs 20.8 min, P < .001) compared with control subjects. Peak minute ventilation, oxygen consumption, and carbon dioxide production were significantly decreased in patients with AN. Heart rate, systolic blood pressure, cardiac index, fractional shortening, and rate-corrected mean velocity of circumferential fiber shortening demonstrated similar patterns of increase with progressive exercise between groups but were decreased at peak exercise in patients with AN. Body mass index percentile, age, peak oxygen consumption, and peak cardiac output were independently associated with exercise duration. CONCLUSIONS: Adolescent patients with AN have reduced exercise capacity and peak cardiovascular indices compared with control subjects but normal patterns of cardiovascular response during progressive exercise. Systolic ventricular function is maintained during exercise in adolescents with AN.

Physiological Responses to Exercise in Pediatric Heart Transplant Recipients.

INTRODUCTION: Pediatric heart transplant (HTx) recipients have reduced exercise capacity typically two-thirds of predicted values, the mechanisms of which are not fully understood. We sought to assess the cardiorespiratory responses to progressive exercise in HTx relative to controls matched for age, sex, body size, and work rate. METHODS: Fourteen HTx recipients and matched controls underwent exercise stress echocardiography on a semisupine cycle ergometer. Hemodynamics, left ventricular (LV) dimensions, and volumes were obtained and indexed to body surface area. Oxygen consumption (V˙O2) was measured, and arteriovenous oxygen difference was estimated using the Fick Principle. RESULTS: At rest, LV mass index (P = 0.03) and volumes (P < 0.001) were significantly smaller in HTx, whereas wall thickness (P < 0.01) and LV mass-to-volume ratio (P = 0.01) were greater. Differences in LV dimensions and stroke volume persisted throughout exercise, but the pattern of response was similar between groups as HR increased. As exercise progressed, heart rate and cardiac index increased to a lesser extent in HTx. Despite this, V˙O2 was similar (P = 0.82) at equivalent work rates as HTx had a greater change in arteriovenous oxygen difference (P < 0.01). CONCLUSIONS: When matched for work rate, HTx had similar metabolic responses to controls despite having smaller LV chambers and an attenuated increase in hemodynamic responses. These findings suggest that HTx may increase peripheral O2 extraction as a compensatory mechanism in response to reduced cardiovascular function.