Increased Arterial Responsiveness to Angiotensin II in Mice Conceived by Assisted Reproductive Technologies.

Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in mice and human offspring (including arterial hypertension, vascular dysfunction, and cardiac remodeling) have become increasingly recognized. Here, we hypothesized that ART may increase arterial responsiveness to angiotensin II (ANG II) by epigenetically modifying the expression of its receptors. To test this hypothesis, we assessed the vasoconstrictor responsiveness to ANG II in isolated aortas from ART and control mice. We also examined ANG II receptor (ATR) type 1 and 2 expression and the promoter methylation of the At1aR, At1bR and At2R genes. We found that the vasoconstrictor response to ANG II was markedly increased in ART mice compared to controls. This exaggerated vasoconstrictor responsiveness in ART mice correlated with a significant increase in the ANG II receptor (ATR) type 1 to ATR type 2 protein expression ratio in the aorta; this was mainly driven by an increase in AT1R expression, and by hypomethylation of two CpG sites located in the At1bR gene promoter leading to increased transcription of the gene. We conclude that in mice, ART increase the vasoconstrictor response to ANG II in the aorta by epigenetically causing an imbalance between the expression of vasoconstrictor (AT1R) and vasodilator (AT2R) ANG II receptors. Unbalanced expression of AT1R and AT2R receptors seems to be a novel mechanism contributing to ART-induced arterial hypertension in mice.

Exaggerated systemic oxidative-inflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression.

KEY POINTS: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative-inflammatory-nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS-) and low-altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. ABSTRACT: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross-sectional study examined to what extent exaggerated systemic oxidative-inflammatory-nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80 m, n = 17), and age- and gender-matched HA dwellers born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 23) and without (CMS-, n = 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone-based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P < 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P < 0.05 vs. CMS-). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

Pulmonary arterial pressure at rest and during exercise in chronic mountain sickness: a meta-analysis.

Up to 10% of the more than 140 million high-altitude dwellers worldwide suffer from chronic mountain sickness (CMS). Patients suffering from this debilitating problem often display increased pulmonary arterial pressure (PAP), which may contribute to exercise intolerance and right heart failure. However, there is little information on the usual PAP in these patients.We systematically reviewed and meta-analysed all data published in English or Spanish until June 2018 on echocardiographic estimations of PAP at rest and during mild exercise in CMS patients.Nine studies comprising 287 participants fulfilled the inclusion criteria. At rest, the point estimate from meta-analysis of the mean systolic PAP was 27.9 mmHg (95% CI 26.3-29.6 mmHg). These values are 11% (+2.7 mmHg) higher than those previously meta-analysed in apparently healthy high-altitude dwellers. During mild exercise (50 W) the difference in mean systolic PAP between patients and high-altitude dwellers was markedly more accentuated (48.3 versus 36.3 mmHg) than at rest.These findings indicate that in patients with CMS PAP is moderately increased at rest, but markedly increased during mild exercise, which will be common with activities of daily living.

SIMBOSPROST: Prevalence of metabolic syndrome and osteoporosis in prostate cancer patients treated with radiotherapy and androgen deprivation therapy: A multicentre, cross-sectional study.

AIM: To assess the prevalence of metabolic syndrome (MetS) and osteoporosis in patients with prostate cancer (PCa) treated with radical radiotherapy (RT) with or without androgen deprivation therapy (ADT). BACKGROUND: Worldwide, the prevalence of MetS is estimated to range from 20% to 25% of the adult population. However, prevalence rates are much higher in PCa patients (pts) who undergo ADT. MATERIALS AND METHODS: Multicentre cross-sectional study of 270 pts in Spain with PCa. Patients were divided into 3 groups based on the duration of ADT (6, 12-18, ≥24 months) and compared to a control group without ADT. MetS was defined according to NCEP ATP III criteria. Osteoporosis was assessed by DEXA. RESULTS: A total of 270 pts, treated from November 2011 to October 2012, were included. Of these, 122 pts (47%) fulfilled the criteria for MetS. The median age of this group was significantly higher (71.3 vs. 69.38 years, p = 0.028). MetS prevalence was 50% in the control group. In pts who received ADT, prevalence was 44.8% after 6 months of ADT, 45.3% after 12-18 months, and 50% after ≥24 months (pns). Most pts (168/270; 62%) underwent DEXA. Of those tested, 78 (46.4%) had osteopenia and only 11 (6.5%) had osteoporosis. CONCLUSIONS: The prevalence of MetS in pts with PCa treated with radical RT was higher (47%) than in the general population. However, there were no significant differences in the duration of ADT administration. The prevalence of osteoporosis was low. These findings suggest that the prevalence of MetS in PCa patients may be higher than previously reported.

Case report of a rare cause of secondary hypertension illustrating the importance of cardio-obstetric preconception counselling.

Background: Cardiovascular diseases represent a leading cause of maternal morbidity and mortality in industrialized countries. High blood pressure during pregnancy is a major driver of short- and long-term cardiovascular health in both mother and child. Screening and adequate treatment of elevated blood pressure before pregnancy significantly reduce mortality risk to mother and child. Case summary: A 30-year-old woman with middle aortic coarctation (MAC) previously treated with aortic stenting was referred to our cardio-obstetrics with plans to become pregnant. The clinical examination revealed severe hypertension with a significant blood pressure gradient between the upper and lower limbs. The patient underwent computed tomography angiography showing re-stenosis of the aorta. After the analysis of the benefit risk of all treatment options, percutaneous transluminal aortic in-stent re-stenting was performed. Following the intervention, blood pressure profile significantly improved but remained slightly elevated further necessitating the introduction of an antihypertensive therapy. Discussion: This clinical case condenses several challenges encountered in the management of hypertension in women who plan to become pregnant. Firstly, it emphasizes the fact that secondary causes of chronic hypertension, including MAC, do not have to be overlooked in childbearing age patient. Secondly, it illustrates the need for a multidisciplinary analysis of all available treatment options in view of a future pregnancy. Finally, it discusses the particular follow-up and potential complications in pregnant women with MAC and aortic stent.

Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy.

BACKGROUND AND AIMS: The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as assessed by flow-mediated dilation (FMD) in patients with acute myocardial infarction (AMI) are unknown. Therefore, we aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT). METHODS: This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PACMAN-AMI trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks. RESULTS: 139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab (n = 68, 5.44 ± 2.24%) versus placebo (n = 71, 5.45 ± 2.19%) group (difference = -0.21%, 95% CI -0.77 to 0.35, p = 0.47). FMD improved throughout 52 weeks in both groups similarly (p < 0.001). There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS) (n = 139, slope = -1.00, p = 0.006), but not with lipid pool (NIRS) (n = 139, slope = -7.36, p = 0.32), or fibrous cap thickness (OCT) (n = 81, slope = -1.57, p = 0.62). CONCLUSIONS: Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness.

Method-comparison study between a watch-like sensor and a cuff-based device for 24-h ambulatory blood pressure monitoring.

The use of 24-h ambulatory blood pressure monitoring (ABPM) has been continuously increasing over the last decades. However, cuff-based devices may cause discomfort, particularly at night, leading to potentially non-representative blood pressure (BP) values. We investigated the feasibility of a cuff-less BP monitoring solution in 67 subjects undergoing conventional 24-h ABPM. A watch-like optical sensor was attached at the upper arm or wrist at the contralateral side of the cuff. Systolic (SBP) and diastolic BP (DBP) values were estimated from the measured optical signals by pulse wave analysis. Average 24-h, daytime and nighttime BP values were compared between the conventional monitor and the cuff-less sensor. The differences between both methods-expressed as mean ± standard deviation (95% limits of agreement)-were of - 1.8 ± 6.2 mmHg (- 13.9, 10.3) on SBP and - 2.3 ± 5.4 mmHg (- 13.0, 8.3) on DBP for 24-h averages, of - 1.5 ± 6.6 mmHg (- 14.4, 11.4) on SBP and - 1.8 ± 5.9 mmHg (- 13.4, 9.9) on DBP for daytime averages, and of 0.4 ± 7.5 mmHg (- 14.4, 15.1) on SBP and - 1.3 ± 6.8 mmHg (- 14.7, 12.0) on DBP for nighttime averages. These results encouragingly suggest that cuff-less 24-h ABPM may soon become a clinical possibility.

Prostate Region-Wise Imaging Biomarker Profiles for Risk Stratification and Biochemical Recurrence Prediction.

BACKGROUND: Identifying prostate cancer (PCa) patients with a worse prognosis and a higher risk of biochemical recurrence (BCR) is essential to guide treatment choices. Here, we aimed to identify possible imaging biomarker (perfusion/diffusion + radiomic features) profiles extracted from MRIs that were able to discriminate patients according to their risk or the occurrence of BCR 10 years after diagnosis, as well as to evaluate their predictive value with or without clinical data. METHODS: Patients with localized PCa receiving neoadjuvant androgen deprivation therapy and radiotherapy were retrospectively evaluated. Imaging features were extracted from MRIs for each prostate region or for the whole gland. Univariate and multivariate analyses were conducted. RESULTS: 128 patients (mean [range] age, 71 [50-83] years) were included. Prostate region-wise imaging biomarker profiles mainly composed of radiomic features allowed discriminating risk groups and patients experiencing BCR. Heterogeneity-related radiomic features were increased in patients with worse prognosis and with BCR. Overall, imaging biomarkers profiles retained good predictive ability (AUC values superior to 0.725 in most cases), which generally improved when clinical data were included (particularly evident for the prediction of the BCR, with AUC values ranging from 0.841 to 0.877 for combined models and sensitivity values above 0.960) and when models were built per prostate region vs. the whole gland. CONCLUSIONS: Prostate region-aware imaging profiles enable identification of patients with worse prognosis and with a higher risk of BCR, retaining higher predictive values when combined with clinical variables.

The Usefulness of Adaptative Radiotherapy in Prostate Cancer: How, When, and Who?

The aim of this study was to develop a deformable image registration (DIR)-based offline ART protocol capable of identifying significant dosimetric changes in the first treatment fractions to determine when adaptive replanning is needed. A total of 240 images (24 planning CT (pCT) and 216 kilovoltage cone-beam CT (CBCT)) were prospectively acquired from 24 patients with prostate adenocarcinoma during the first three weeks of their treatment (76 Gy in 38 fractions). This set of images was used to plan a hypofractionated virtual treatment (57.3 Gy in 15 fractions); correlation with the DIR of pCT and each CBCT allowed to translate planned doses to each CBCT, and finally mapped back to the pCT to compare with those actually administered. In 37.5% of patients, doses administered in 50% of the rectum (D50) would have exceeded the dose limitation to 50% of the rectum (R50). We first observed a significant variation of the planned rectal volume in the CBCTs of fractions 1, 3, and 5. Then, we found a significant relationship between the D50 accumulated in fractions 1, 3, and 5 and the lack of compliance with the R50. Finally, we found that a D50 variation rate [100 × (administered D50 − planned D50/planned D50)] > 1% in fraction three can reliably identify variations in administered doses that will lead to exceeding rectal dose constraint.

EPR spectroscopic evidence of iron-catalysed free radical formation in chronic mountain sickness: Dietary causes and vascular consequences.

Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free 'catalytic' iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = -0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+. TRIAL REGISTRY: ClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.

Cardiac Phenotypes in Secondary Hypertension: JACC State-of-the-Art Review.

Several forms of secondary hypertension carry a high risk of cardiac morbidity and mortality. Evaluation of cardiac phenotypes in secondary hypertension provides a unique opportunity to study underlying hormonal and biochemical mechanisms affecting the heart. We review the characteristics of cardiac dysfunction in different forms of secondary hypertension and clarify the mechanisms behind the higher prevalence of heart damage in these patients than in those with primary hypertension. Attention to the specific clinical/biochemical phenotypes of these conditions may assist clinicians to screen for and confirm secondary forms of hypertension. Thereby, early signs of heart damage can be recognized and monitored, allowing individualized treatment to delay or prevent evolution toward more advanced disease.

The Impact of Frailty Screening on Radiation Treatment Modification.

BACKGROUND: Care overburden makes it difficult to perform comprehensive geriatric assessments (CGAs) in oncology settings. We analyzed if screening tools modified radiotherapy in oncogeriatric patients. METHODS: Patients ≥ 65 years, irradiated between December 2020 and March 2021 at the Hospital Provincial de Castellón, completed the frailty G8 and estimated survival Charlson questionnaires. The cohort was stratified between G8 score ≤ 14 (fragile) or >14 (robust); the cutoff point for the Charlson index was established at five. RESULTS: Of 161 patients; 69.4% were male, the median age was 75 years (range 65-91), and the prevailing performance status (PS) was 0-1 (83.1%). Overall, 28.7% of the cohort were frail based on G8 scores, while the estimated survival at 10 years was 2.25% based on the Charlson test. The treatment administered changed up to 21% after frailty analysis. The therapies prescribed were 5.8 times more likely to be modified in frail patients based on the G8 test. In addition, patients ≥ 85 years (p = 0.01), a PS ≥ 2 (p = 0.008), and limited mobility (p = 0.024) were also associated with a potential change. CONCLUSIONS: CGAs remain the optimal assessment tool in oncogeriatry. However, we found that the G8 fragility screening test, which is easier to integrate into patient consultations, is a reliable and efficient aid to rapid decision making.

[Nutritional impact of radiotherapy in oncogeriatric patients. Can radiation oncologists minimize the radiotherapy impact on the nutritional status of the elderly patient?] / Repercusión de la radioterapia sobre la situación nutricional del paciente oncogeriátrico. ¿Puede el oncólogo radioterápico minimizar el impacto de la radioterapia sobre el estado nutricional del enfermo mayor?

INTRODUCTION: Cancer in elderly patients represents a global health challenge due to the increase in its incidence and its associated mortality. In our country it is the second leading cause of death in people over 65 years. In the coming years, the problem will increase, with a prognosis of people over 65 years of 35% in 2050. Radiotherapy is an essential part of the multidisciplinary treatment of cancer in elderly patients, where sometimes it is considered as the first therapeutic option and others, as an alternative to surgery and/or chemotherapy if they pose too much risk. The technological development of Radiation Oncology in recent years has allowed optimizing treatments and reducing side effects in elderly patients, who tend to have a higher incidence of comorbidities. It is essential that professionals involved in the multidisciplinary treatment of cancer know the possible toxicity and its management in oncogeriatric patients; otherwise, the percentage of patients who do not receive radiotherapy despite of an adequate indication will not decrease. In this sense, it is necessary to recognize those patients who may suffer from malnutrition or are at risk of suffering it, to initiate a nutritional intervention that minimizes weight loss that alters or even causes the suspension of the planned treatment.

INTRODUCCIÓN: RESUMEN El cáncer en pacientes ancianos representa un reto de salud a escala mundial debido al aumento de su incidencia y su mortalidad asociada. En nuestro país es la segunda causa de muerte en mayores de 65 años. En años venideros el problema irá en aumento, con un pronóstico de personas mayores de 65 años del 35% en el año 2050. La radioterapia supone una parte fundamental del tratamiento multidisciplinar del cáncer en los pacientes ancianos, donde unas veces se plantea como primera opción terapéutica y otras, como alternativa a la cirugía y/o la quimioterapia si estas plantean demasiado riesgo. El desarrollo tecnológico de la Oncología Radioterápica en los últimos años ha permitido optimizar los tratamientos y disminuir las toxicidades en los pacientes de edad avanzada, que suelen presentar mayor incidencia de comorbilidades. Es fundamental que los profesionales implicados en el tratamiento multidisciplinar del cáncer conozcan la posible toxicidad y su manejo en los pacientes oncogeriátricos, ya que, de lo contrario, disminuyen las probabilidades de que pacientes con indicación adecuada de este tratamiento lo reciban. En este sentido, es imprescindible el reconocimiento de aquellos pacientes que puedan sufrir desnutrición o estén en riesgo de sufrirla, para iniciar una intervención nutricional que minimice una pérdida de peso que altere o incluso haga suspender el tratamiento planificado.

Association of Assisted Reproductive Technologies With Arterial Hypertension During Adolescence.

BACKGROUND: Assisted reproductive technologies (ART) have been shown to induce premature vascular aging in apparently healthy children. In mice, ART-induced premature vascular aging evolves into arterial hypertension. Given the young age of the human ART group, long-term sequelae of ART-induced alterations of the cardiovascular phenotype are unknown. OBJECTIVES: This study hypothesized that vascular alterations persist in adolescents and young adults conceived by ART and that arterial hypertension possibly represents the first detectable clinically relevant endpoint in this group. METHODS: Five years after the initial assessment, the study investigators reassessed vascular function and performed 24-h ambulatory blood pressure (BP) monitoring (ABPM) in 54 young, apparently healthy participants conceived through ART and 43 age- and sex-matched controls. RESULTS: Premature vascular aging persisted in ART-conceived subjects, as evidenced by a roughly 25% impairment of flow-mediated dilation of the brachial artery (p < 0.001) and increased pulse-wave velocity and carotid intima-media thickness. Most importantly, ABPM values (systolic BP, 119.8 ± 9.1 mm Hg vs. 115.7 ± 7.0 mm Hg, p = 0.03; diastolic BP, 71.4 ± 6.1 mm Hg vs. 69.1 ± 4.2 mm Hg, p = 0.02 ART vs. control) and BP variability were markedly higher in ART-conceived subjects than in control subjects. Eight of the 52 ART participants, but only 1 of the 43 control participants (p = 0.041 ART vs. controls) fulfilled ABPM criteria of arterial hypertension (>130/80 mm Hg and/or >95th percentile). CONCLUSIONS: ART-induced premature vascular aging persists in apparently healthy adolescents and young adults without any other detectable classical cardiovascular risk factors and progresses to arterial hypertension. (Vascular Dysfunction in Offspring of Assisted Reproduction Technologies; NCT00837642.).

Assisted Reproductive Technologies Predispose to Insulin Resistance and Obesity in Male Mice Challenged With a High-Fat Diet.

Assisted reproductive technology (ART) alters glucose homeostasis in mice and humans, but the underlying mechanisms are incompletely understood. ART induces endothelial dysfunction and arterial hypertension by epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene. In eNOS-deficient mice, insulin resistance is related to impaired insulin stimulation of muscle blood flow and substrate delivery and defective intrinsic skeletal muscle glucose uptake. We therefore assessed glucose tolerance, insulin sensitivity (euglycemic clamp), insulin stimulation of muscle blood flow in vivo, and muscle glucose uptake in vitro in male ART and control mice fed a normal chow (NC) or challenged with a high-fat diet (HFD) during 8 weeks. Glucose tolerance and insulin sensitivity were similar in NC-fed animals. When challenged with a HFD, however, ART mice developed exaggerated obesity, fasting hyperinsulinemia and hyperglycemia, and a 20% lower insulin-stimulated glucose utilization than did control mice (steady-state glucose infusion rate (GIR), 51.3 ± 7.3 vs 64.0 ± 10.8 mg/kg/min, P = 0.012). ART-induced insulin resistance was associated with defective insulin stimulation of muscle blood flow, whereas intrinsic skeletal muscle glucose uptake was normal. In conclusion, ART-induced endothelial dysfunction, when challenged with a metabolic stress, facilitates glucose intolerance and insulin resistance. Similar mechanisms may contribute to ART-induced alterations of the metabolic phenotype in humans.

Pulmonary artery pressure and arterial oxygen saturation in people living at high or low altitude: systematic review and meta-analysis.

More than 140 million people are living at high altitude worldwide. An increase of pulmonary artery pressure (PAP) is a hallmark of high-altitude exposure and, if pronounced, may be associated with important morbidity and mortality. Surprisingly, there is little information on the usual PAP in high-altitude populations. We, therefore, conducted a systematic review (MEDLINE and EMBASE) and meta-analysis of studies published (in English or Spanish) between 2000 and 2015 on echocardiographic estimations of PAP and measurements of arterial oxygen saturation in apparently healthy participants from general populations of high-altitude dwellers (>2,500 m). For comparison, we similarly analyzed data published on these variables during the same period for populations living at low altitude. Twelve high-altitude studies comprising 834 participants and 18 low-altitude studies (710 participants) fulfilled the inclusion criteria. All but one high-altitude studies were performed between 3,600 and 4,350 m. The combined mean systolic PAP (right ventricular-to-right atrial pressure gradient) at high altitude [25.3 mmHg, 95% confidence interval (CI) 24.0, 26.7], as expected was significantly (P < 0.001) higher than at low altitude (18.4 mmHg, 95% CI 17.1,19.7), and arterial oxygen saturation was significantly lower (90.4%, 95% CI 89.3, 91.5) than at low altitude (98.1%; 95% CI 97.7, 98.4). These findings indicate that at an altitude where the very large majority of high-altitude populations are living, pulmonary hypertension appears to be rare. The reference values and distributions for PAP and arterial oxygen saturation in apparently healthy high-altitude dwellers provided by this meta-analysis will be useful to future studies on the adjustments to high altitude in humans.

Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice.

We previously demonstrated that the sodium/hydrogen exchanger NHA2, also known as NHEDC2 or SLC9B2, is critical for insulin secretion by ß-cells. To gain more insights into the role of NHA2 on systemic glucose homeostasis, we studied the impact of loss of NHA2 during the physiological aging process and in the setting of diet-induced obesity. While glucose tolerance was normal at 2 months of age, NHA2 KO mice displayed a significant glucose intolerance at 5 and 12 months of age, respectively. An obesogenic high fat diet further exacerbated the glucose intolerance of NHA2 KO mice. Insulin levels remained similar in NHA2 KO and WT mice during aging and high fat diet, but fasting insulin/glucose ratios were significantly lower in NHA2 KO mice. Peripheral insulin sensitivity, measured by insulin tolerance tests and hyperinsulinemic euglycemic clamps, was unaffected by loss of NHA2 during aging and high fat diet. High fat diet diminished insulin secretion capacity in both WT and NHA2 KO islets and reduced expression of NHA2 in WT islets. In contrast, aging was characterized by a gradual increase of NHA2 expression in islets, paralleled by an increasing difference in insulin secretion between WT and NHA2 KO islets. In summary, our results demonstrate that loss of the sodium/hydrogen exchanger NHA2 exacerbates obesity- and aging-induced glucose intolerance in mice. Furthermore, our data reveal a close link between NHA2 expression and insulin secretion capacity in islets.

Sleep-Disordered Breathing and Vascular Function in Patients With Chronic Mountain Sickness and Healthy High-Altitude Dwellers.

BACKGROUND: Chronic mountain sickness (CMS) is often associated with vascular dysfunction, but the underlying mechanism is unknown. Sleep-disordered breathing (SDB) frequently occurs at high altitude. At low altitude, SDB causes vascular dysfunction. Moreover, in SDB, transient elevations of right-sided cardiac pressure may cause right-to-left shunting in the presence of a patent foramen ovale (PFO) and, in turn, further aggravate hypoxemia and pulmonary hypertension. We speculated that SDB and nocturnal hypoxemia are more pronounced in patients with CMS compared with healthy high-altitude dwellers, and are related to vascular dysfunction. METHODS: We performed overnight sleep recordings, and measured systemic and pulmonary artery pressure in 23 patients with CMS (mean ± SD age, 52.8 ± 9.8 y) and 12 healthy control subjects (47.8 ± 7.8 y) at 3,600 m. In a subgroup of 15 subjects with SDB, we assessed the presence of a PFO with transesophageal echocardiography. RESULTS: The major new findings were that in patients with CMS, (1) SDB and nocturnal hypoxemia was more severe (P < .01) than in control subjects (apnea-hypopnea index [AHI], 38.9 ± 25.5 vs 14.3 ± 7.8 number of events per hour [nb/h]; arterial oxygen saturation, 80.2% ± 3.6% vs 86.8% ± 1.7%, CMS vs control group), and (2) AHI was directly correlated with systemic blood pressure (r = 0.5216; P = .001) and pulmonary artery pressure (r = 0.4497; P = .024). PFO was associated with more severe SDB (AHI, 48.8 ± 24.7 vs 14.8 ± 7.3 nb/h; P = .013, PFO vs no PFO) and hypoxemia. CONCLUSIONS: SDB and nocturnal hypoxemia are more severe in patients with CMS than in control subjects and are associated with systemic and pulmonary vascular dysfunction. The presence of a PFO appeared to further aggravate SDB. Closure of the PFO may improve SDB, hypoxemia, and vascular dysfunction in patients with CMS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.