Vascular Dysfunction In Children Research Articles

Correction: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

Nowak KL, Farmer-Bailey H, Wang W, You Z, Steele C, Cadnapaphornchai MA, Klawitter J, Patel N, George D, Jovanovich A, Soranno DE, Gitomer B, Chonchol M: Curcumin therapy to treat vascular dysfunction in children and young adults with ADPKD: A randomized controlled trial. Clin J Am Soc Nephrol 17: [

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

An Overview of Vascular Dysfunction and Determinants: The Case of Children of African Ancestry.

The balance between dilatory and constrictive factors is important as it keeps blood vessels in a homeostatic state. However, altered physiological processes as a result of obesity, hypertension, oxidative stress, and other cardiovascular risk factors may lead to vascular damage, causing an imbalance of vasoactive factors. Over time, the sustained imbalance of these vasoactive factors may lead to vascular dysfunction, which can be assessed by non-invasive methods, such as flow-mediated dilation, pulse wave velocity, flow-mediated slowing, retinal vessel analysis, peripheral vascular reactivity, and carotid intima-media thickness assessment. Although there is increasing prevalence of cardiovascular risk factors (obesity and hypertension) in children in sub-Saharan Africa, little is known about how this may affect vascular function. This review focuses on vasoactive factors implicated in vascular (dys)function, highlighting the determinants and consequences of vascular dysfunction. It further describes the non-invasive methods used for vascular (dys)function assessments and, last, describes the impact of cardiovascular risk factors on vascular dysfunction in children of African ancestry.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Design and Baseline Characteristics of Participants

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Design and Baseline Characteristics of Participants

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants

Although often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6–25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.

Vascular dysfunction of postural tachycardia syndrome in children.

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance, and its incidence in children is approximately 6.8% [1]. The pathogenesis of POTS is complex with multiple, overlapping, interacting pathophysiological mechanisms. Although the specific pathogenic mechanism has remained perplexing, with the discovery of various gasotransmitters and biological peptides, the vascular dysfunction has aroused overwhelming attention. On the basis of searching in a wide range of recent original literatures, we reviewed the pathogenesis of vascular dysfunction in children with POTS. The flow-mediated vasodilation of POTS patients was greater than that of healthy controls, and the vasodilator factors were increased in patients with POTS under basal condition or under a standing position, while the vasoconstriction factors were reduced. Vascular dysfunction, as one of pathogenesis in pediatric POTS patients, affects the occurrence and development of diseases through a variety of factors.

Vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease.

Adults with autosomal dominant polycystic kidney disease (ADPKD) exhibit vascular dysfunction, as evidenced by impaired endothelium-dependent dilation (EDD) and stiffening of the large elastic arteries. However, it is unknown whether vascular dysfunction begins earlier in the course of ADPKD. The aim of the study was to assess EDD and arterial stiffness in children and young adults with ADPKD. Fifteen children and young adults 6–22 years of age with ADPKD and normal renal function were prospectively recruited for participation in a cross-sectional study. Fifteen healthy controls were enrolled to match cases for age and sex. The primary outcomes were EDD, measured as brachial artery flow-mediated dilation (FMDBA), and arterial stiffness, measured as carotid-femoral pulse wave velocity (CFPWV). ADPKD cases were more likely to be taking an angiotensin-converting enzyme inhibitor, but otherwise did not differ from controls in clinical characteristics, including blood pressure. FMDBA was 25% lower in children and young adults with ADPKD (7.7 ± 0.9%, mean ± SE) when compared with matched controls (10.2 ± 0.8%) (P < 0.05). CFPWV was 14% higher in children and young adults with ADPKD (544 ± 23 cm/s) when compared with matched controls (478 ± 17 cm/s) (P < 0.05). Secondary measures of arterial stiffness, carotid augmentation index and carotid systolic blood pressure were also increased in cases when compared with controls (P < 0.05). Impaired EDD and increased arterial stiffness, important independent predictors of future cardiovascular events and mortality, are evident very early in the course of ADPKD in the presence of normal kidney function. Novel interventions to reduce vascular dysfunction in children and young adults with ADPKD should be evaluated, as childhood and young adulthood may represent a critical therapeutic window to reduce future cardiovascular risk in patients with ADPKD.

Vascular dysfunction in children conceived by assisted reproductive technologies: underlying mechanisms and future implications.

Epidemiological studies in humans have demonstrated a relationship between pathological events during fetal development and increased cardiovascular risk later in life and have led to the so called "Fetal programming of cardiovascular disease hypothesis". The recent observation of generalised vascular dysfunction in young apparently healthy children conceived by assisted reproductive technologies (ART) provides a novel and potentially very important example of this hypothesis. This review summarises recent data in ART children demonstrating premature subclinical atherosclerosis in the systemic circulation and pulmonary vascular dysfunction predisposing to exaggerated hypoxia-induced pulmonary hypertension. These problems appear to be related to the ART procedure per se. Studies in ART mice demonstrating premature vascular aging and arterial hypertension further demonstrate the potential of ART to increase cardiovascular risk and have allowed to unravel epigenetic alterations of the eNOS gene as an underpinning mechanism. The roughly 25% shortening of the life span in ART mice challenged with a western style high-fat-diet demonstrates the potential importance of these alterations for the long-term outcome. Given the young age of the ART population, data on cardiovascular endpoints will not be available before 20 to 30 years from now. However, already now cohort studies of the ART population are needed to early detect cardiovascular alterations with the aim to prevent or at least optimally treat cardiovascular complications. Finally, a debate needs to be engaged on the future of ART and the consequences of its exponential growth for public health.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Shortened life span in mice generated by in vitro fertilization

In humans assisted reproductive technologies (ART) induce generalized vascular dysfunction in children. In line with this observation, ART induces vascular dysfunction and arterial hypertension in mice that is related to an epigenetic mechanism, but the long term consequences are unknown. To address this problem, we compared the long term survival of ART and control mice fed a normal chow diet (NC) or challenged with a high‐fat diet (HFD).80 male FVB mice generated by ART and 80 control mice born and raised in our animal facility were observed in these studies. Three to four animals were placed in a cage in the clean conventional mouse facility. 6 ART and 7 control mice had to be sacrificed because of injuries related to fighting. 32 ART and 20 control mice were fed NC, 42 ART mice and 53 control mice were fed a HFD (49.5% fat, 31.5% protein and 0% carbohydrate). Kaplan‐Meier survival curves were constructed using known birth and death dates and the log‐rank test was used to evaluate statistical differences between groups.We found that in mice fed with NC the life span was similar in the two groups. In contrast, HFD, while not having a detectable effect on life span in control mice, reduced the survival in ART‐mice by roughly 25%(P&lt;0.0001).ART is associated with a marked reduction of the life span in normal mice challenged with a Western style high‐fat diet.

Letter by Andreassi Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”

HomeCirculationVol. 127, No. 9Letter by Andreassi Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies” Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLetter by Andreassi Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies” Maria Grazia Andreassi, MSc, PhD Maria Grazia AndreassiMaria Grazia Andreassi CNR, Institute of Clinical PhysiologyPisa, Italy Search for more papers by this author Originally published5 Mar 2013https://doi.org/10.1161/CIRCULATIONAHA.112.113357Circulation. 2013;127:e475To the Editor:In a recent issue of Circulation, the elegant manuscript by Scherrer et al1 reported a marked vascular dysfunction of the systemic and pulmonary circulation in healthy children and adolescents conceived by using assisted reproductive technologies (ARTs). As mentioned in the article, epigenetic mechanisms may play a key role in regulating gene expression at the vascular level. Epigenetics refers to modifications (DNA methylation and specific histone tail post-translational modifications) of the genome without change in primary DNA sequence, that can be inherited both mitotically and meiotically. Although results from animal studies indicate that ARTs are associated with epigenetic alternations, data in humans are inconsistent and great caution is recommended in extrapolating these findings to humans.2 Furthermore, a very recent study did not find evidence of aberrant methylation on a genome-wide level as well as no differences in percentage of methylation of 8 candidate genes.3 These results corroborate an earlier study that found no increase of epigenetic abnormalities in a cohort of 5891 neonates conceived by intracytoplasmic sperm injection.3 Therefore, it still remains unclear whether more subtle changes in DNA methylation occur commonly, leading to differences in gene expression and clinical phenotypes in ART children.3 On the other hand, much evidence supports the possibility that DNA damage in a gamete (oocytes and sperm cells) or in an embryo, to the different phases of an ART treatment (eg, fertility drugs, in vitro culture), may impact the embryo development or have long-lasting developmental consequences. For instance, ovarian stimulation in ART treatments induces the development and growth of multiple follicles, resulting in high numbers of oocytes associated with an increased chromosomal DNA error rate, especially in women aged ≤40 years. In addition, the integrity of sperm DNA is of crucial importance in the clinic use for ART.4 Only those spermatozoa with normal morphology, motility, and normal sperm DNA damage are selected and considered to be good sperm cells for clinical use. Such sperm parameters, however, do not ensure for a total DNA integrity. Spermatozoa with highly damaged DNA may have a negative impact on the health of the offspring later in life, as animal studies have shown that spermatozoa DNA-fragmented spermatozoa can transmit genetic defects leading to a long-term manifestation of a variety of deleterious phenotypes, such as aberrant growth, premature aging, abnormal behavior, and tumors.4 Of particular relevance for vascular dysfunction may be the DNA damage associated with critically shortened telomeres in germ cells. Research carried out over the last 10 years has demonstrated the relevance of shortened telomeres in vascular disorders and cardiac events. In fact, an activated DNA response pathway induced by both oxidative DNA damage and telomere dysfunction is believed to be the crucial mediator for increased premature vascular aging or apoptosis, playing a pathogenetic role in atherosclerosis.5Additional research is thus needed to define causal pathways between ART-related health problems and both prenatal epigenetic and genetic alterations, and their possible relevance to subtle cardiovascular consequences reported in ART offspring.The study by Scherrer et al1 highlights the importance of elucidating the molecular and cellular mechanisms that contribute to increase all potential cardiovascular risks associated with the use of reproductive technology.Maria Grazia Andreassi MSc, PhDCNR, Institute of Clinical PhysiologyPisa, ItalyDisclosuresNone.

Letter by Irion Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”

To the Editor: I read with interest the article by Scherrer et al.1 This research was largely advertised in a Swiss television show, 36.9, on April 4, 2012.2 In this show, it was clearly evident that …

Response to Letters Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”

We thank Philips and O’Leary for their interesting comments on our study. They suggest that considering pubertal maturation as a potential confounding factor would have been important for the interpretation of the results, because it has been reported that in prepubertal boys, pulse-wave velocity is lower than in prepubertal girls, a difference that disappears after puberty.1 In our study, the very large majority of the participants was prepubertal, the mean age of the group conceived by assisted reproductive technologies (ART) tended to be lower, and there were proportionally more boys than girls in this group. Taken together, the combination of these factors would have been expected to result in lower pulse-wave velocity in the ART group than in the control group. This is exactly the opposite of what we found, which suggests that we may even have underestimated the detrimental effects …

Letter by Phillips and O’Leary Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”

To the Editor: We congratulate Scherrer et al1 for their interesting work describing pulmonary, cardiac, and vascular dysfunction in children conceived through the ever-more-prevalent assisted reproductive technology. Surely this work sheds light on the potential for lasting cardiovascular effects of conception and gestation. We also value the use of arteriosclerotic markers in children, and would like to highlight some important considerations that would help in interpreting these intriguing findings.2 It is clear that careful planning and laborious effort went into the extensive cardiovascular assessment, as well as the thorough …

Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies

Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7 ± 1.6% versus 8.6 ± 1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

Endothelial progenitor cells and vascular dysfunction in children with obstructive sleep apnea.

Endothelial dysfunction is a potential complication of obstructive sleep apnea syndrome (OSAS) in children ascribed to systemic inflammatory changes. However, not all children with OSAS will manifest endothelial dysfunction. The variability in endothelial function in pediatric OSAS may be related to the ability to recruit repair mechanisms such as endothelial progenitor cells (EPCs). Prepubertal nonhypertensive children with or without polysomonographically confirmed OSAS had endothelial function assessed in a morning fasted state using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries. Blood was drawn and EPCs were assessed by flow cytometry and triple staining using antibodies against CD133, CD34, and vascular endothelial growth factor receptor-2 after isolation of peripheral blood mononuclear cells. SDF-1 levels were measured by ELISA. Eighty children with OSAS (mean age 8.2 +/- 1.4 yr, mean body mass index [BMI] z-score, 1.43 +/- 0.3) and 20 controls (CO) matched for BMI, age, sex, and ethnicity were studied. Significant delays to peak capillary reperfusion after occlusion release (Tmax) occurred in OSAS children, but substantial variability was present. Despite similar OSAS severity, EPC counts, and stromal cell-derived factor-1 (SDF-1) levels were significantly lower among the 20 OSAS children with the longest Tmax, when compared with either the 20 children with normal Tmax values or to CO ( P < 0.01). Furthermore, Tmax was significantly and inversely correlated with EPCs (r(2), 0.51; P < 0.01), but neither EPCs nor Tmax were associated with apnea-hyponea index (AHI). Endothelial dysfunction is frequently present in OSAS. Variance in endothelial functional phenotype may not only reside in the individual susceptibility but also in the ability to recruit endothelial repair mechanisms.

Inflammatory and thrombotic processes are associated with vascular dysfunction in children with familial hypercholesterolemia

Background Evidence suggests that children with familial hypercholesterolemia (FH) have endothelial dysfunction. Inflammatory and haemostatic abnormalities are associated with advanced atherosclerosis and increased cardiovascular events. However, it is unknown whether these abnormalities present in FH children and contribute to their vascular dysfunction. Methods and results We studied 38 children with FH (19 males, 19 females aged 14.8 ± 0.9 years mean ± S.E.) and 41 healthy children (controls; 22 males, 19 females aged 15.4 ± 0.7 years). Endothelium-dependent reactive hyperemia (RH%) and endothelium-independent nitrate hyperemia dilatation (NH%) were measured by strain gauge plethysmography. Inflammatory and haemostatic parameters were assessed by ELISA. RH% and NH% were significantly reduced in FH compared to controls (91.3 ± 9.3% vs. 120.4 ± 10.6% and 53.6 ± 3.8% vs. 74.5 ± 7.4%, p < 0.05 for both). Total cholesterol and lipoprotein (a) were increased in FH children compared to controls (282.3 ± 8.8 mg/dl vs. 163.8 ± 4.6 mg/dl and 11.0[4.6, 30.7] mg/dl vs. 5.24[2.63, 11.0] mg/dl median [IQR] respectively; p < 0.001 for both). Intercellular cell adhesion molecule (ICAM-1) and interleukin 1β (IL-1β) serum levels were increased in FH compared to controls ( p < 0.05 and <0.001, respectively). Plasminogen activator inhibitor 1 (PAI-1) levels were also higher in FH children ( p < 0.001). Multivariate analysis revealed that reactive hyperemia was independently associated with nitrate-dependent reactive hyperemia ( β = 0.597(0.199), p < 0.01), PAI-1( β = −6.78(2.65), p < 0.05), log IL-1β ( β = −102.8 (30.2), p < 0.01), age ( β = −5.06 (2.35), p < 0.05) and FH status ( β = −25.2(10.6), p < 0.05) ( R 2 for the model: 0.63, p = 0.001). Conclusions Inflammatory and haemostatic abnormalities are present in FH children and contribute to the endothelial dysfunction observed in these children.

Effects of diet and exercise on obesity-related vascular dysfunction in children

Effects of diet and exercise on obesity-related vascular dysfunction in children