Epidemiological studies have shown an association between pathologic events occurring during fetal/perinatal life and the development of cardiovascular and metabolic disease in adulthood. These observations have led to the so-called developmental origin of adult disease hypothesis. More recently, evidence has been provided that the pulmonary circulation is also an important target for the developmental programming of adult disease in both experimental animal models and in humans. Here we will review this evidence and provide insight into mechanisms that may play a pathogenic role.

HomeCirculationVol. 127, No. 9Response to Letters 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/EPUBResponse to Letters Regarding Article, "Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies" Urs Scherrer, MD, Stefano F. Rimoldi, MD, Emrush Rexhaj, MD and Thomas Stuber, MD Hervé Duplain, MD and Sophie Garcin, MD Stefano F. de Marchi, MD Pascal Nicod, MD Marc Germond, MD Yves Allemann, MD and Claudio Sartori, MD Urs ScherrerUrs Scherrer Swiss Cardiovascular CenterBern University HospitalBern, Switzerland , Stefano F. RimoldiStefano F. Rimoldi Swiss Cardiovascular CenterBern University HospitalBern, Switzerland , Emrush RexhajEmrush Rexhaj Swiss Cardiovascular CenterBern University HospitalBern, Switzerland and Thomas StuberThomas Stuber Swiss Cardiovascular CenterBern University HospitalBern, Switzerland Hervé DuplainHervé Duplain Botnar Center for Extreme Medicine and Department of Internal MedicineCHUVLausanne, Switzerland and Sophie GarcinSophie Garcin Botnar Center for Extreme Medicine and Department of Internal MedicineCHUVLausanne, Switzerland Stefano F. de MarchiStefano F. de Marchi Swiss Cardiovascular CenterBern University HospitalBern, Switzerland Pascal NicodPascal Nicod Hirslanden GroupLausanne, Switzerland Marc GermondMarc Germond Centre de Procréation Médicalement AssistéeLausanne, Switzerland Yves AllemannYves Allemann Swiss Cardiovascular CenterBern University HospitalBern, Switzerland and Claudio SartoriClaudio Sartori Swiss Cardiovascular CenterBern University HospitalBern, Switzerland Originally published5 Mar 2013https://doi.org/10.1161/CIRCULATIONAHA.112.134833Circulation. 2013;127:e478We 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 of ART on this variable. They also suggest that the influence of estrogens should be considered. As noted above, there were only a few peripubescent girls included in our study. Moreover, to the best of our knowledge, there is no published evidence indicating that flow-mediated dilation increases between prepubertal and postpubertal girls. In line with this concept, age was not related to flow-mediated dilation in the girls included in our study. We would like to take the opportunity to indicate that in the few postpubertal girls included in our study, vascular function was tested during the early follicular phase (day 1–7 of the menstrual cycle), because vascular responsiveness varies during the menstrual cycle.2 Thus, we are confident that endogenous feminizing hormones were not a confounding factor in our study. Finally, they suggest that overweight should have been considered. We are very well aware of the effects of obesity on cardiovascular and metabolic regulation3,4; however, there were no overweight participants in our study. In summary, we are very confident that the large differences in vascular function and vascular morphology between these young ART and control children are valid and related to the ART procedure. Future studies that plan to examine older and/or obese participants should take into account the suggestions by Philips and O'Leary when interpreting the data.Dr Andreassi suggests to be cautious about extrapolating findings showing epigenetic alterations in ART mice to humans and refers to studies that did not find alterations of DNA methylation in peripheral blood samples obtained from ART children. While we agree that one has to be cautious when extrapolating from one species to another, it is nevertheless intriguing that ART induces vascular dysfunction in offspring of sterile humans and normal fertile mice.5 Moreover, preliminary data in mice suggest that ART-induced epigenetic alterations may be tissue specific and therefore undetectable when searching for alterations of DNA methylation in whole blood samples or amnion/chorion tissue.6 We are confident that our study will greatly stimulate research on the potential role of epigenetic and other mechanisms such as alterations of telomere length proposed by Dr Andreassi to find ways to prevent ART-induced vascular dysfunction in the future.Dr Irion wonders whether the fact of being informed about the study hypothesis may have altered the findings. As requested by the ethics committee, participants were informed about the hypothesis that ART may alter vascular responsiveness (no mention about future risk of myocardial infarction was made, since this issue was not tested in our study). To the best of our knowledge, there is no published evidence that emotional stress of short duration alters carotid intima media thickness or hypoxia-induced pulmonary hypertension. Mental stress increases flow-mediated dilation in healthy young subjects.7 If, as suggested by Dr Irion, ART children were more stressed than control children, we may even have underestimated the effects of ART on flow-mediated dilation.Urs Scherrer, MDStefano F. Rimoldi, MDEmrush Rexhaj, MDThomas Stuber, MDSwiss Cardiovascular CenterBern University HospitalBern, SwitzerlandHervé Duplain, MDSophie Garcin, MDBotnar Center for Extreme Medicine andDepartment of Internal MedicineCHUVLausanne, SwitzerlandStefano F. de Marchi, MDSwiss Cardiovascular CenterBern University HospitalBern, SwitzerlandPascal Nicod, MDHirslanden GroupLausanne, SwitzerlandMarc Germond, MDCentre de Procréation Médicalement AssistéeLausanne, SwitzerlandYves Allemann, MDClaudio Sartori, MDSwiss Cardiovascular CenterBern University HospitalBern, SwitzerlandDisclosuresNone.References1. Ahimastos AA, Formosa M, Dart AM, Kingwell BA. Gender differences in large artery stiffness pre- and post puberty.J Clin Endocrinol Metab. 2003; 88:5375–5380.CrossrefMedlineGoogle Scholar2. Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K, Komesaroff PA. Variations in endothelial function and arterial compliance during the menstrual cycle.J Clin Endocrinol Metab. 2001; 86:5389–5395.CrossrefMedlineGoogle Scholar3. Scherrer U, Randin D, Tappy L, Vollenweider P, Jéquier E, Nicod P. Body fat and sympathetic nerve activity in healthy subjects.Circulation. 1994; 89:2634–2640.LinkGoogle Scholar4. Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity.Circulation. 1997; 96:4104–4113.LinkGoogle Scholar5. Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garcin S, de Marchi SF, Nicod P, Germond M, Allemann Y, Sartori C. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.Circulation. 2012; 125:1890–1896.LinkGoogle Scholar6. Oliver VF, Miles HL, Cutfield WS, Hofman PL, Ludgate JL, Morison IM. Defects in imprinting and genome-wide DNA methylation are not common in the in vitro fertilization population.Fertil Steril. 2012; 97:147–53.e7.CrossrefMedlineGoogle Scholar7. Harris CW, Edwards JL, Baruch A, Riley WA, Pusser BE, Rejeski WJ, Herrington DM. Effects of mental stress on brachial artery flow-mediated vasodilation in healthy normal individuals.Am Heart J. 2000; 139:405–411.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 5, 2013Vol 127, Issue 9 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.134833PMID: 23580976 Originally publishedMarch 5, 2013 PDF download Advertisement

BACKGROUND: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.METHODS AND RESULTS: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.CONCLUSIONS: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.CLINICAL TRIAL REGISTRATION:URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.

Background: Systolic right ventricular (RV) function is an important predictor in the course of various congenital and acquired heart diseases. Its practical determination by echocardiography remains challenging. We compared routine assessment of lateral tricuspid annular systolic motion velocity (TV(lat), cm/s) using pulsed-wave tissue Doppler imaging from the apical 4-chamber view with cardiac magnetic resonance (CMR) as reference method.Methods and results: 254 individuals (43 +/- 18 years) underwent both CMR (contiguous short axis slices; retrogated cine steady state free precession technique; manual contour tracing) and echocardiography within 2 +/- 2 months. Seventy-five had coronary artery disease, 87 congenital heart disease, 17 dilated cardiomyopathy, 15 pulmonary artery hypertension, and 47 normal findings. RV ejection fraction (EF) by CMR was 51 +/- 12% (range 17-78%). There was a linear correlation between RVEF and TV(lat) (r = 0.60; p<0.0001). A TV(lat) cut-off of 12 cm/s identified patients with normal EF (>= 50%) with 81% sensitivity and 68% specificity, and a threshold of TV(lat) <9 cm/s identified patients with severely reduced RVEF (<30%) with 82% sensitivity and 86% specificity.Conclusions: Systolic long-axis velocity measurements of the lateral tricuspid annulus allow a reliable assessment of RVEF in clinical routine. A threshold of TV(lat) <9 cm/s identifies patients with severely reduced RVEF (<30%) with high sensitivity and specificity. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Autonomic Stimulation Promotes AFCL Gradients in AF. Introduction: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high‐frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect.

Autonomic Stimulation Induces PV Ectopy and AF. Introduction: The induction of atrial fibrillation (AF) by pulmonary vein (PV) ectopy is well described. The triggers for these PV ectopy are not so well understood. The intrinsic cardiac autonomic nervous system (ANS) has been suggested as a potential upstream regulator that may cause PV ectopy and atrial fibrillation (AF). We hypothesized that activation of the ANS by high frequency stimulation (HFS) of atrial ganglionated plexi (GP) can initiate PV ectopy.Methods and Results: During sinus rhythm in 12 patients undergoing ablation for paroxysmal AF, short bursts of HFS, synchronized to the local atrial refractory period, were delivered at presumed GP sites. Electrograms were recorded from catheters placed in the PV, coronary sinus (CS) and high right atrium (HRA). A total of 112 episodes of HFS were recorded, producing ectopic activity in 91 of 112 (81%) episodes. Of these 91 episodes, there were 46 episodes of isolated single ectopic beats, 5 episodes of double ectopic responses, 24 episodes of ectopy/tachycardia lasting <30 s, and 16 episodes of AF lasting >30 s. In 63 of 91 episodes, the PV catheter was placed adjacent to the stimulated GP, resulting in ectopy recorded earliest in the PV catheter in 48 of 63 (76%) episodes. In one patient, reproducible ectopy was shown to occur following AV nodal conduction delay in response to HFS. Without HFS, neither AV nodal conduction delay nor ectopy occurred.Conclusions: This study has demonstrated a direct link between activation of the intrinsic cardiac autonomic nervous system and pulmonary vein ectopy in humans. (J Cardiovasc Electrophysiol, Vol. 22, pp. 638-646, June 2011)

This study aims to evaluate a method to detect heart rate variability (HRV) changes using short ECG segments during ablation for arrhythmias.

HomeCirculationVol. 123, No. 11Response to Letters Regarding Article, “Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia” Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Letters Regarding Article, “Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia” Stefano F. Rimoldi, MD, Pierre-Yves Jayet, MD, Emrush Rexhaj, MD, Sébastien Thalmann, MD, Marcos Schwab, MD, Pierre Turini, MD, Céline Sartori-Cucchia, RN, Pascal Nicod, MD, Urs Scherrer, MD and Claudio Sartori, MD Damian Hutter, MD, Thomas Stuber, MD and Yves Allemann, MD Carlos Salinas Salmòn, MD and Mercedes Villena, MD Stefano F. RimoldiStefano F. Rimoldi Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Pierre-Yves JayetPierre-Yves Jayet Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Emrush RexhajEmrush Rexhaj Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Sébastien ThalmannSébastien Thalmann Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Marcos SchwabMarcos Schwab Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Pierre TuriniPierre Turini Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Céline Sartori-CucchiaCéline Sartori-Cucchia Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Pascal NicodPascal Nicod Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author , Urs ScherrerUrs Scherrer Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author and Claudio SartoriClaudio Sartori Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, Switzerland (Rimoldi, Jayet, Rexhaj, Thalmann, Schwab, Turini, Sartori-Cucchia, Nicod, Scherrer, Sartori) Search for more papers by this author Damian HutterDamian Hutter Swiss Cardiovascular Center Bern University Hospital, Bern Bern, Switzerland (Hutter, Stuber, Allemann) Search for more papers by this author , Thomas StuberThomas Stuber Swiss Cardiovascular Center Bern University Hospital, Bern Bern, Switzerland (Hutter, Stuber, Allemann) Search for more papers by this author and Yves AllemannYves Allemann Swiss Cardiovascular Center Bern University Hospital, Bern Bern, Switzerland (Hutter, Stuber, Allemann) Search for more papers by this author Carlos Salinas SalmònCarlos Salinas Salmòn Instituto Boliviano de Biologia de Altura La Paz, Bolivia (Salmòn, Villena) Search for more papers by this author and Mercedes VillenaMercedes Villena Instituto Boliviano de Biologia de Altura La Paz, Bolivia (Salmòn, Villena) Search for more papers by this author Originally published22 Mar 2011https://doi.org/10.1161/CIRCULATIONAHA.110.003939Circulation. 2011;123:e387We thank Lazdam et al and Yuan et al for their interesting comments on our study.1 Lazdam et al point out that in our study, birth weight in offspring of mothers with preeclampsia was significantly lower than in controls, and suggest that the vascular impairment in offspring was caused by a combination of the independent effects of preeclampsia and intrauterine growth restriction rather than by preeclampsia per se. To test this hypothesis, we performed a subgroup analysis of 15 offspring of mothers with preeclampsia and 15 controls matched for birth weight (3080±291 versus 3077±398 g; P=0.98). We found that the difference in flow-mediated dilation between birth-weight-matched offspring of preeclampsia and controls (6.4%±1.3% versus 8.9%±1.2%; P<0.0001) tended to be even larger than the one we reported in the entire groups (6.3%±1.2% versus 8.3%±1.6%; P<0.0001). This additional analysis, together with the already reported lack of any significant relationship between birth weight and flow-mediated dilation, indicates that vascular dysfunction in these young offspring is related to preeclampsia alone, and that low birth weight does not contribute to this problem. We therefore do not overestimate the impact of preeclampsia on vascular function in these term offspring.Lazdam et al also ask for information on other aspects of vascular function and are surprised that we found no significant differences in peripheral blood pressure between these young offspring of mothers with preeclampsia and controls. First, we wish to note here that it took large epidemiological studies to demonstrate small, albeit statistically significant, differences in peripheral blood pressure between offspring of preeclampsia and controls.2 Most importantly, in 24 offspring of preeclampsia and 27 controls we measured central blood pressure by tonometry (SphygmoCor, AtCor Medical, Sydney, Australia) and found that systolic (97.2±6.8 versus 97.8±9.3 mm Hg; P=0.79) and diastolic (76.3±7.1 versus 73.0±7.1 mm Hg; P=0.74) central blood pressure was comparable. We also assessed carotid-femoral pulse wave velocity (Complior Device, Alam Medical, Vincennes, France) in these subgroups and found that it was similar in offspring of preeclampsia and controls (6.6±1.1 versus 6.2±1.2 m/s; P=0.25). These findings indicate that, in contrast to flow-mediated dilation, peripheral and central blood pressure and pulse wave velocity are still normal in young offspring of preeclampsia. These important additional data suggest that endothelial dysfunction represents the very first step in the development of arteriosclerosis3 predisposing to premature cardiovascular disease in offspring of preeclampsia.Yuan et al suggest that vascular dysfunction in offspring of preeclampsia is related to low physical activity. Although we did not directly assess physical activity in our study, we do not have any evidence that could be consistent with this hypothesis. For example, low physical activity would be expected to be associated with an increased body mass index in offspring of preeclampsia, the opposite of what we found in our study. Siblings often have comparable physical activity; in our study, siblings of offspring of mothers with preeclampsia who were born after normal pregnancy had perfectly normal vascular function. Finally, resting heart rate was comparable in offspring and controls. We are very confident that the large differences in vascular function between offspring of preeclampsia and controls are not related to differences in physical activity, but to preeclampsia alone.Stefano F. Rimoldi, MDPierre-Yves Jayet, MDEmrush Rexhaj, MDSébastien Thalmann, MDMarcos Schwab, MDPierre Turini, MDCéline Sartori-Cucchia, RNPascal Nicod, MDUrs Scherrer, MDClaudio Sartori, MD Department of Internal Medicine and Botnar Center for Extreme Medicine University Hospital, Lausanne Lausanne, SwitzerlandDamian Hutter, MDThomas Stuber, MDYves Allemann, MD Swiss Cardiovascular Center Bern University Hospital, Bern Bern, SwitzerlandCarlos Salinas Salmòn, MDMercedes Villena, MD Instituto Boliviano de Biologia de Altura La Paz, BoliviaDisclosuresNone.References1. Jayet PY, Rimoldi SF, Stuber T, Salmon CS, Hutter D, Rexhaj E, Thalmann S, Schwab M, Turini P, Sartori-Cucchia C, Nicod P, Villena M, Allemann Y, Scherrer U, Sartori C. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation. 2010; 122:488–494.LinkGoogle Scholar2. Ferreira I, Peeters LL, Stehouwer CDA. Preeclampsia and increased blood pressure in the offspring: meta-analysis and critical review of the evidence. J Hypertens. 2009; 27:1955–1959.CrossrefMedlineGoogle Scholar3. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115:1285–1295.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 22, 2011Vol 123, Issue 11 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.003939 Originally publishedMarch 22, 2011 PDF download Advertisement SubjectsPeripheral Vascular Disease

OBJECTIVE: Although a history of previous acute mountain sickness (AMS) is commonly used for providing advice and recommending its prophylaxis during subsequent exposure, the intraindividual reproducibility of AMS during repeated high-altitude exposure has never been examined in a prospective controlled study. METHODS: In 27 nonacclimatized children and 29 adults, AMS was assessed during the first 48 hours after rapid ascent to 3450 m on 2 consecutive occasions 9 to 12 months apart. RESULTS: During the first exposure, 18 adults (62%) and 6 children (22%) suffered from AMS; during the second exposure, 14 adults (48%) and 4 children (15%) suffered from this problem (adults versus children, P ≤ .01). Most importantly, the intraindividual reproducibility of AMS was very different (P < .001) between children and adults. None of the 6 children having suffered from AMS during the first exposure suffered from AMS during the second exposure, but 4 children with no AMS during the first exposure did experience this problem during the second exposure. In contrast, 14 of the 18 adults who suffered from AMS on the first occasion also presented with this problem during the second exposure, and no new case developed in those who had not experienced AMS on the first occasion. CONCLUSIONS: In adults, a history of AMS is highly predictable of the disease on subsequent exposure, whereas in children it has no predictive value. A history of AMS should not prompt practitioners to advise against reexposure to high altitude or to prescribe drugs for its prophylaxis in children.

In our recent article in CHEST,1Stuber T Sartori C Schwab M et al.Exaggerated pulmonary hypertension during mild exercise in chronic mountain sickness.Chest. 2010; 137: 388-392Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar we suggested that in patients suffering from chronic mountain disease (CMS), the exaggerated increase in pulmonary-artery pressure during mild exercise is not related to a difference in the extent of the pulmonary microcirculation because carbon monoxide diffusing capacity was comparable in patients with CMS and control subjects.1Stuber T Sartori C Schwab M et al.Exaggerated pulmonary hypertension during mild exercise in chronic mountain sickness.Chest. 2010; 137: 388-392Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Johnson suggests that to reinforce this conclusion, the data should be analyzed further and reported as percent predicted values adjusted for lung volume. Percent predicted carbon monoxide diffusing capacity (143% ± 22% vs 157% ± 25%, P = .15), carbon monoxide diffusing capacity per unit of alveolar volume (137% ± 13% vs 130% ± 23%, P = .30), carbon monoxide diffusing capacity adjusted for lung volume (142% ± 20% vs 143% ± 23%, P = .92), and carbon monoxide diffusing capacity per unit of alveolar volume adjusted for lung volume (137% ± 14% vs 145% ± 23%, P = .29) were similar in patients with CMS and control subjects. These additional data further strenghten our conclusion that the large differences in pulmonary-artery pressure responsiveness between patients with CMS and healthy control subjects are not related to differences in the pulmonary microcirculation between the two groups. Association of Chronic Mountain Sickness With Abnormal Pulmonary Microcirculation: Importance of Adjusting Predicted Diffusing Capacity of the Lung for Carbon Monoxide for Altitude, Hemoglobin, and Lung VolumeCHESTVol. 138Issue 3PreviewA recent issue of CHEST (February 2010) published findings by Stuber et al1 of large increases in pulmonary hypertension with mild exercise in chronic mountain sickness (CMS). It is important, however, to know whether the findings are associated with abnormal pulmonary microcirculation (using diffusing capacity of the lung for carbon monoxide [Dlco] as proxy). To better evaluate whether CMS has abnormal gas exchange, the authors should report Dlco as percent predicted and properly adjust it for lung volume. Full-Text PDF

About 30 million people live above 2500 m in the Andean Mountains of South America. Among them are 5.5 million Aymaras, an ethnic group with its own language, living on the altiplano of Bolivia, Peru, and northern Chile at altitudes of up to 4400 m. In this high altitude region traces of human population go back for more than 2000 years with constant evolutionary pressure on its residents for genetic adaptation to high altitude. Aymaras as the assumed direct descendents of the ancient cultures living in this region were the focus of much research interest during the last decades and several distinctive adaptation patterns to life at high altitude have been described in this ethnic group. The aim of this article was to review the physiology and pathophysiology of circulatory adaptation and maladaptation to longtime altitude exposure in Aymaras and Caucasians.

BACKGROUND:Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced.METHODS:We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m.RESULTS:The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001).CONCLUSIONS:Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.

Background— Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results— We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3±1.2% versus 8.3±1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=−0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid–reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. Conclusions— Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

OBJECTIVE. Acute mountain sickness is a frequent and debilitating complication of high-altitude exposure, but there is little information on the prevalence and time course of acute mountain sickness in children and adolescents after rapid ascent by mechanical transportation to 3500 m, an altitude at which major tourist destinations are located throughout the world. METHODS. We performed serial assessments of acute mountain sickness (Lake Louise scores) in 48 healthy nonacclimatized children and adolescents (mean ± SD age: 13.7 ± 0.3 years; 20 girls and 28 boys), with no previous high-altitude experience, 6, 18, and 42 hours after arrival at the Jungfraujoch high-altitude research station (3450 m), which was reached through a 2.5-hour train ascent. RESULTS. We found that the overall prevalence of acute mountain sickness during the first 3 days at high altitude was 37.5%. Rates were similar for the 2 genders and decreased progressively during the stay (25% at 6 hours, 21% at 18 hours, and 8% at 42 hours). None of the subjects needed to be evacuated to lower altitude. Five subjects needed symptomatic treatment and responded well. CONCLUSION. After rapid ascent to high altitude, the prevalence of acute mountain sickness in children and adolescents was relatively low; the clinical manifestations were benign and resolved rapidly. These findings suggest that, for the majority of healthy nonacclimatized children and adolescents, travel to 3500 m is safe and pharmacologic prophylaxis for acute mountain sickness is not needed.

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden death In young adults. On the basis of histopathologicat findings its pathogenesis may involve both a genetic origin and an inflammatory process. Bortonella henselae may cause endomyocarditis and was detected in myocardium from a young male who succumbed to sudden cardiac death. Hypothesis: We hypothesized that chronic infection with Bartonella henselae could contribute to the pathogenesis of ARVC.Methods: We investigated sera from 49 patients with ARVC for IgG antibodies to Bartonella henselae. In this study, 58 Swiss blood donors tested by the same method served as controls.Results: Six patients with ARVC (12%) had positive (>1:256) IgG titres in the immunofluorescence test with Bartonella henselae. In contrast, only 1 elevated titre was found in 58 controls (P <0.05). Interestingly, all patients with increased titres had no familial occurrence of ARVC.Conclusions: Further studies in larger patient cohorts seem justified to investigate a possible causal link between chronic Bortonella henselae and ARVC, in particular its sporadic (nonfamilial) form.

Acute mountain sickness (AMS) is a frequent and debilitating complication of high‐altitude exposure. After a rapid ascent to tourist destinations located above 3000 m, as many as 60% of an adult population are affected. Circumstantial evidence suggests that children and teenagers may be even more susceptible to AMS than adults, but direct evidence is lacking. We, therefore, performed serial assessments of AMS (Lake Louise Score, LLS) in 48 teenagers (mean±SD age, 13.7±0.3 yrs; 20 girls and 28 boys) 6, 24, 48 hrs after arrival at the Jungfraujoch high‐altitude research station (3454 m) reached after a 2 hr ascent by train. The major new finding was that 6 hrs after arrival, AMS (LLS≥3) was present in only 22% of the subjects (mean score 4.1±0.4, range 3–7). The incidence of AMS was similar in both genders and steadily declined during the stay (17% at 24 hrs, 8% at 48 hrs). None of the subjects needed pharmacological treatment other than paracetamol. In conclusion, in teenagers the incidence of AMS after rapid arrival at an altitude where major high‐altitude tourist destinations are located world‐wide, is surprisingly low, benign, and resolves rapidly. These findings challenge the notion that teenagers are more susceptible to AMS than adults. They suggest that for the vast majority of teenagers, travel to these altitudes is safe and does not necessitate pharmacological prophylaxis for AMS.Grant support: Swiss National Science Foundation.

Journal of Cardiovascular ElectrophysiologyVolume 19, Issue 5 p. 566-567 Ultra Rapid Local Activity in Adenosine-Induced Atrial Fibrillation THOMAS STUBER M.D., THOMAS STUBER M.D. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorPHANG BOON LIM M.B., B.CH., PHANG BOON LIM M.B., B.CH. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorMARK D. O'NEILL M.B., B.CH., D.PHIL., MARK D. O'NEILL M.B., B.CH., D.PHIL. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorNICHOLAS S. PETERS M.D., F.R.C.P., NICHOLAS S. PETERS M.D., F.R.C.P. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this author THOMAS STUBER M.D., THOMAS STUBER M.D. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorPHANG BOON LIM M.B., B.CH., PHANG BOON LIM M.B., B.CH. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorMARK D. O'NEILL M.B., B.CH., D.PHIL., MARK D. O'NEILL M.B., B.CH., D.PHIL. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this authorNICHOLAS S. PETERS M.D., F.R.C.P., NICHOLAS S. PETERS M.D., F.R.C.P. St. Mary's Hospital and Imperial College of Medicine, London, UKSearch for more papers by this author First published: 08 July 2008 https://doi.org/10.1111/j.1540-8167.2007.01044.xCitations: 1 Address for correspondence: Thomas Stuber, Department of Cardiology, St. Mary's Hospital, Praed Street, London W2 1NY, United Kingdom. Fax: +44 2078861657; E-mail: t.stuber@imperial.ac.uk J Cardiovasc Electrophysiol, Vol. 19, pp. 566–567, May 2008. Thomas Stuber is supported by the Swiss National Science Foundation; Phang Boon Lim is supported by the British Heart Foundation. Dr. Peters received honoraria for speaking on this topic. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume19, Issue5May 2008Pages 566-567 RelatedInformation