Increased ferroptosis in leukocytes from preeclamptic women involving the long non-coding taurine upregulated gene 1 (TUG1).

BACKGROUND: Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non-coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells. METHODS: We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE. RESULTS: We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti-ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti-inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22-24 weeks were strongly associated with the development of PE. CONCLUSIONS: Our findings suggest that maternal leukocytes in PE show decreased anti-ferroptotic activity that correlates with anti-inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE.

Hypertensive disorders of pregnancy among women with cardiovascular disease in Norway: A historical cohort study.

INTRODUCTION: Women with cardiovascular disease may be at increased risk of hypertensive disorders of pregnancy (HDP). We aimed to: (1) Investigate the occurrence of HDP in a cohort of pregnant women with cardiovascular disease and compare it with the occurrence in the general population. (2) Assess the association between maternal cardiovascular risk and risk of HDP. MATERIAL AND METHODS: We reviewed clinical data on a cohort of 901 pregnancies among 708 women with cardiovascular disease who were followed at the National Unit for Pregnancy and Heart Disease and gave birth at Oslo University Hospital between 2003 and 2018. The exposure under study was maternal cardiovascular risk, classified as low, moderate, or high based on a modified classification by the World Health Organization. The main outcome of interest was HDP, which included pre-eclampsia and gestational hypertension. The proportion of HDP cases in the general population in the same period was extracted from the Medical Birth Registry of Norway. We used logistic regression to estimate crude and adjusted odds ratios (OR) of HDP, with associated 95% confidence intervals (CIs), for women with moderate- and high cardiovascular risk compared to women with low risk. RESULTS: The occurrence of HDP in the study cohort was 12.1% (95% CI: 10.0%-14.4%) and varied between 8.7% (95% CI: 6.5%-11.3%) in the low-risk group, 15.7% (95% CI: 11.1%-21.4%) in the moderate-risk group, and 22.2% (95% CI: 15.1%-30.8%) in the high-risk group. By contrast, the nationwide occurrence of HDP was 5.1% (95% CI: 5.1%-5.2%). In the study cohort, the proportions of pregnancies with gestational hypertension and pre-eclampsia were similar (6.3% and 5.8%, respectively). Compared to pregnancies with low cardiovascular risk, the adjusted OR of HDP was 2.04 (95% CI: 1.21-3.44) in the moderate-risk group and 2.99 (95% CI: 1.73-5.18) in the high-risk group. CONCLUSIONS: The occurrence of hypertensive disease of pregnancy in the study cohort was more than doubled compared to the general population in Norway. The risk of HDP increased with maternal cardiovascular risk group. We recommend taking into account maternal cardiovascular risk group when assessing risk and prophylaxis of HDP.

Maternal beta-blocker dose and risk of small-for gestational-age in women with heart disease.

INTRODUCTION: Beta-blockers are prescribed for many pregnant women with heart disease, but whether there is a dose-dependent effect on fetal growth remains to be examined. We aimed to investigate if antenatal beta-blocker use and dose were associated with delivering a small-for-gestational-age infant among women with heart disease. MATERIAL AND METHODS: Our cohort included women with heart disease who delivered at Oslo University Hospital between 2006 and 2015. Maternal heart disease was classified into modified WHO risk scores. Women with beta-blocker treatment were dichotomized into whether they had been treated with a low or high dose based on clinical factors. We compared the risk of delivering a small-for-gestational-age infant in women exposed to high doses, low doses, or with no exposure to antenatal beta-blockers while adjusting for severity of maternal heart disease in logistic regression models. RESULTS: Of a total of 540 pregnancies among women with heart disease, 163 (30.2%) were exposed to beta-blocker treatment. The majority were treated with metoprolol (86.5%). Almost twice as many babies in the beta-blocker group were small-for-gestational-age, compared with the non-exposed group (19.8 vs 9.5%, P < 0.001). Women using a high-dose beta-blocker had a five-fold increased risk of delivering a small-for-gestational-age infant compared with non-exposure (adjusted odds ratio [aOR] 4.89, 95% confidence interval [CI] 2.22-10.78, P < 0.001). Women using a low dose of beta-blocker had a two-fold increased risk of delivering a small-for-gestational-age infant; however, the confidence interval included the null (aOR 1.75, 95% CI 0.83-3.72, P = 0.143). Results when restricting the analyses to metoprolol showed the same pattern, but with attenuation of risks. CONCLUSIONS: We found a five-fold increased risk of delivering a small-for-gestational-age infant in women with heart disease treated with a high dose of beta-blocker, and a two-fold increased risk among those treated with a low dose, showing an apparent dose-response relation. Close monitoring of fetal growth is warranted among women with heart disease treated with beta-blockers. As drug therapy in pregnancy concerns both mother and fetus, an optimum balance for both should be the goal.

Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study.

BACKGROUND: Eisenmenger syndrome is associated with substantial morbidity and mortality. There is no consensus, however, on mortality risk stratification. We aimed to investigate survival and predictors of death in a large, contemporary cohort of Eisenmenger syndrome patients. METHODS: In a multicenter approach, we identified adults with Eisenmenger syndrome under follow-up between 2000 and 2015. We examined survival and its association with clinical, electrocardiographic, echocardiographic, and laboratory parameters. RESULTS: We studied 1098 patients (median age, 34.4 years; range, 16.1-84.4 years; 65.1% female; 31.9% with Down syndrome). The majority had a posttricuspid defect (n=643, 58.6%), followed by patients with a complex (n=315, 28.7%) and pretricuspid lesion (n=140, 12.7%). Over a median follow-up of 3.1 years (interquartile range, 1.4-5.9), allowing for 4361.6 patient-years observation, 278 patients died and 6 underwent transplantation. Twelve parameters emerged as significant predictors of death on univariable analysis. On multivariable Cox regression analysis, only age (hazard ratio [HR], 1.41/10 years; 95% confidence interval [CI], 1.24-1.59; P<0.001), pretricuspid shunt (HR, 1.56; 95% CI, 1.02-2.39; P=0.041), oxygen saturation at rest (HR, 0.53/10%; 95% CI, 0.43-0.65; P<0.001), presence of sinus rhythm (HR, 0.53; 95% CI, 0.32-0.88; P=0.013), and presence of pericardial effusion (HR, 2.41; 95% CI, 1.59-3.66; P<0.001) remained significant predictors of death. CONCLUSIONS: There is significant premature mortality among contemporary adults with Eisenmenger syndrome. We report, herewith, a multivariable mortality risk stratification model based on 5 simple, noninvasive predictors of death in this population.

Past and current cause-specific mortality in Eisenmenger syndrome.

AIMS: Eisenmenger syndrome (ES) is associated with considerable morbidity and mortality. Therapeutic strategies have changed during the 2000s in conjunction with an emphasis on specialist follow-up. The aim of this study was to determine the cause-specific mortality in ES and evaluate any relevant changes between 1977 and 2015. METHODS AND RESULTS: This is a retrospective, descriptive multicentre study. A total of 1546 patients (mean age 38.7 ± 15.4 years; 36% male) from 13 countries were included. Cause-specific mortality was examined before and after July 2006, 'early' and 'late', respectively. Over a median follow-up of 6.1 years (interquartile range 2.1-21.5 years) 558 deaths were recorded; cause-specific mortality was identified in 411 (74%) cases. Leading causes of death were heart failure (34%), infection (26%), sudden cardiac death (10%), thromboembolism (8%), haemorrhage (7%), and peri-procedural (7%). Heart failure deaths increased in the 'late' relative to the 'early' era (P = 0.032), whereas death from thromboembolic events and death in relation to cardiac and non-cardiac procedures decreased (P = 0.014, P = 0.014, P = 0.004, respectively). There was an increase in longevity in the 'late' vs. 'early' era (median survival 52.3 vs. 35.2 years, P < 0.001). CONCLUSION: The study shows that despite changes in therapy, care, and follow-up of ES in tertiary care centres, all-cause mortality including cardiac remains high. Patients from the 'late' era, however, die later and from chronic rather than acute cardiac causes, primarily heart failure, whereas peri-procedural and deaths due to haemoptysis have become less common. Lifelong vigilance in tertiary centres and further research for ES are clearly needed.

Mitral Valve Segmentation and Tracking from Transthoracic Echocardiography Using Deep Learning.

OBJECTIVE: Valvular heart diseases (VHDs) pose a significant public health burden, and deciding the best treatment strategy necessitates accurate assessment of heart valve function. Transthoracic echocardiography (TTE) is the key modality to evaluate VHDs, but the lack of standardized quantitative measurements leads to subjective and time-consuming assessments. We aimed to use deep learning to automate the extraction of mitral valve (MV) leaflets and annular hinge points from echocardiograms of the MV, improving standardization and reducing workload in quantitative assessment of MV disease. METHODS: We annotated the MV leaflets and annulus points in 2931 images from 127 patients. We propose an approach for segmenting the annotated features using Attention UNet with deep supervision and weight scheduling of the attention coefficients to enforce saliency surrounding the MV. The derived segmentation masks were used to extract quantitative biomarkers for specific MV leaflet scallops throughout the heart cycle. RESULTS: Evaluation performance was summarized using a Dice score of 0.63 ± 0.14, annulus error of 3.64 ± 2.53 and leaflet angle error of 8.7 ± 8.3°. Leveraging Attention UNet with deep supervision robustness of clinically relevant metrics was improved compared with UNet, reducing standard deviations by 2.7° (angle error) and 0.73 mm (annulus error). We correctly identified cases of MV prolapse, cases of stenosis and healthy references from a clinical material using the derived biomarkers. CONCLUSION: Robust deep learning segmentation and tracking of MV morphology and motion is possible by leveraging attention gates and deep supervision, and holds promise for enhancing VHD diagnosis and treatment monitoring.

Anxiety and Depression in Adults With Congenital Heart Disease.

BACKGROUND: A comprehensive understanding of adult congenital heart disease outcomes must include psychological functioning. Our multisite study offered the opportunity to explore depression and anxiety symptoms within a global sample. OBJECTIVES: In this substudy of the APPROACH-IS (Assessment of Patterns of Patient-Reported Outcomes in Adults With Congenital Heart Disease-International Study), the authors we investigated the prevalence of elevated depression and anxiety symptoms, explored associated sociodemographic and medical factors, and examined how quality of life (QOL) and health status (HS) differ according to the degree of psychological symptoms. METHODS: Participants completed the Hospital Anxiety and Depression Scale, which includes subscales for symptoms of anxiety (HADS-A) and depression (HADS-D). Subscale scores of 8 or higher indicate clinically elevated symptoms and can be further categorized as mild, moderate, or severe. Participants also completed analogue scales on a scale of 0 to 100 for QOL and HS. Analysis of variance was performed to investigate whether QOL and HS differed by symptom category. RESULTS: Of 3,815 participants from 15 countries (age 34.8 ± 12.9 years; 52.7% female), 1,148 (30.1%) had elevated symptoms in one or both subscales: elevated HADS-A only (18.3%), elevated HADS-D only (2.9%), or elevations on both subscales (8.9%). Percentages varied among countries. Both QOL and HS decreased in accordance with increasing HADS-A and HADS-D symptom categories (P < 0.001). CONCLUSIONS: In this global sample of adults with congenital heart disease, almost one-third reported elevated symptoms of depression and/or anxiety, which in turn were associated with lower QOL and HS. We strongly advocate for the implementation of strategies to recognize and manage psychological distress in clinical settings. (Patient-Reported Outcomes in Adults With Congenital Heart Disease [APPROACH-IS]; NCT02150603).

Cardiorespiratory fitness in women after severe pre-eclampsia.

AIMS: To objectively study cardiorespiratory fitness (CRF) and physical activity (PA) and to evaluate limiting factors of exercise intolerance associated with poor CRF after severe pre-eclampsia. METHODS: In this single-centre, cross-sectional study, CRF was measured as peak oxygen uptake (VO2peak) during a cardiopulmonary exercise test (CPET) on a treadmill in women 7 years after severe pre-eclampsia. Ninety-six patients and 65 controls were eligible to participate. Cardiac output (CO) was measured by impedance cardiography. PA was measured using accelerometers. RESULTS: In 62 patients and 35 controls (mean age 40 ± 3 years), the VO2peak (in mL·kg-1·min-1) values were 31.4 ± 7.2 and 39.1 ± 5.4, respectively (p<0.01). In the patients, the COpeak was (9.6 L·min-1), 16% lower compared to controls (p<0.01). Twelve patients (19%) had a cardiac limitation to CPET. Twenty-three (37%) patients and one (3%) control were classed as unfit, with no cardiopulmonary limitations. The patients demonstrated 25% lower PA level (in counts per minute; p<0.01) and 14% more time being sedentary (p<0.01), compared with the controls. Twenty-one patients (34%) compared with four (17%) controls did not meet the World Health Organization's recommendations for PA (p=0.02). Body mass index and PA level accounted for 65% of the variability in VO2peak. CONCLUSION: Significantly lower CRF and PA levels were found in patients on long-term follow-up after severe pre-eclampsia. CPET identified cardiovascular limitations in one third of patients. One third appeared unfit, with adiposity and lower PA levels. These findings highlight the need for clinical follow-up and exercise interventions after severe pre-eclampsia.

High prevalence of pre-eclampsia in women with coarctation of the aorta.

Aims: The aim was to study pregnancy outcomes in women with coarctation of the aorta (CoA) and associations to hypertensive disorders of pregnancy. Maternal morbidity and mortality are higher in women with heart disease and pre-eclampsia. Chronic hypertension, frequently encountered in CoA, is a risk factor for pre-eclampsia. Methods and results: Clinical data from the National Unit for Pregnancy and Heart Disease database was reviewed for pregnant women with CoA from 2008 to 2021. The primary outcome was hypertensive pregnancy disorders. The secondary outcomes were other cardiovascular, obstetric, and foetal complications. Seventy-six patients were included, with a total of 87 pregnancies. Seventeen (20%) patients were treated for chronic hypertension before pregnancy. Fifteen (20%) patients developed pre-eclampsia, and 5 (7%) had pregnancy-induced hypertension. Major adverse cardiac events developed in four (5%) patients, with no maternal or foetal mortality. Maternal age at first pregnancy [odds ratio (OR) 1.37], body mass index before first pregnancy (OR 1.77), and using acetylsalicylic acid from the first trimester (OR 0.22) were statistically significantly associated with pre-eclampsia. At follow-up (median) 8 years after pregnancy, 29 (38%) patients had anti-hypertensive treatment, an increase of 16% compared to pre-pregnancy. Five (7%) patients had progression of aorta ascendens dilatation to >40 mm, seven (9%) had an upper to lower systolic blood pressure gradient >20 mmHg, and six (8%) had received CoA re-intervention. Conclusion: Pre-eclampsia occurred in 20% of women with CoA in their first pregnancy. All pre-eclamptic patients received adequate anti-hypertensive treatment. All CoA patients were provided multi-disciplinary management, including cardiologic follow-up, to optimize maternal-foetal outcomes.

Adult congenital heart disease training in Europe: current status, disparities and potential solutions.

OBJECTIVES: This study aimed to determine the status of training of adult congenital heart disease (ACHD) cardiologists in Europe. METHODS: A questionnaire was sent to ACHD cardiologists from 34 European countries. RESULTS: Representatives from 31 of 34 countries (91%) responded. ACHD cardiology was recognised by the respective ministry of Health in two countries (7%) as a subspecialty. Two countries (7%) have formally recognised ACHD training programmes, 15 (48%) have informal (neither accredited nor certified) training and 14 (45%) have very limited or no programme. Twenty-five countries (81%) described training ACHD doctors 'on the job'. The median number of ACHD centres per country was 4 (range 0-28), median number of ACHD surgical centres was 3 (0-26) and the median number of ACHD training centres was 2 (range 0-28). An established exit examination in ACHD was conducted in only one country (3%) and formal certification provided by two countries (7%). ACHD cardiologist number versus gross domestic product Pearson correlation coefficient=0.789 (p<0.001). CONCLUSION: Formal or accredited training in ACHD is rare among European countries. Many countries have very limited or no training and resort to 'train people on the job'. Few countries provide either an exit examination or certification. Efforts to harmonise training and establish standards in exit examination and certification may improve training and consequently promote the alignment of high-quality patient care.

Is experienced pregnancy in women with repaired tetralogy of Fallot related to diffuse myocardial fibrosis?

OBJECTIVES: To assess the impact of pregnancy on cardiac function and fibrosis by cardiovascular magnetic resonance (CMR) in patients with repaired Tetralogy of Fallot (rToF). BACKGROUND: CMR T1 mapping can assess diffuse myocardial fibrosis which is associated to adverse clinical outcomes. Right ventricular (RV) accelerated remodeling is reported in rToF women with experienced pregnancy. METHODS: We included rToF women from the national registry of congenital heart disease to perform CMR, assessing functional data, T1 mapping/ extracellular volume fraction (ECV). The results including clinical data were compared between women with experienced pregnancy vs non-experienced pregnancy and healthy individuals. RESULTS: Fifty rToF women performed CMR, median age 36 (range 21-67) years. Fifteen were nulliparous. T1 mapping was compared to 30 controls, (14 women) median age 42 (24-64) years. In the left ventricle (LV), T1 times and ECV in all rToF women vs female controls were 1248 ± 61 ms/ 25.8 ± 2.9% vs 1255 ± 40 ms/ 26.8 ± 3.1%, p = 0.7 and p = 0.3, respectively. In rToF, RV T1 times was 1385 ± 124 ms and ECV 37.7 ± 5.4%. There was no association to parity or age in rToF LV T1/ ECV, p = 0.9 for both, or RV T1/ECV, p = 0.4 and p = 0.6, respectively. Indexed LV mass was higher in the rToF pregnancy group, 43 ± 10 vs 38 ± 6 g/m2, p = 0.03 while RV ejection fraction was lower, 49 ± 7% vs 53 ± 6%, p = 0.04. CONCLUSION: Women with rTOF showed evidence of increased RV CMR markers suggestive of diffuse fibrosis while LV CMR markers were within normal values. Having experienced pregnancy might affect RV function, however without association to CMR biomarkers.

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies.

OBJECTIVE: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental wingless (Wnt) pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia. METHODS: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study [n = 10 in each group, RNA sequencing (RNAseq)] to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months postpartum from an acute preeclampsia study (preeclampsia n = 34, normal pregnancy n = 61). RESULTS: We found circulating and placental mRNA levels of the secreted Wnt agonist R-spondin 3 (RSPO3) at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the noncanonical Ca/NFAT pathway. Finally, plasma dickkopf 3 was decreased in preeclampsia 6 months postpartum. CONCLUSION: We identify a potential role for RSPO3 and activation of noncanonical Wnt signaling in preeclampsia.

Vascular function in adults with cyanotic congenital heart disease.

BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. METHODS: This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. RESULTS: Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p < 0.0001), however preserved FMD response compared to controls (106.5 ± 8.3% vs. 106.4 ± 6.1%, p = 0.95). In contrast, NID was lower in the patients (110.5 ± 6.1% vs. 115.1 ± 7.4%, p = 0.053). There was no difference in CIMT, carotid plaque or cPT-max. The patients presented with lower high-density-lipoprotein cholesterol, and higher level of inflammatory markers and S1P. CONCLUSION: Adults with CCHD had preserved FMD in the brachial artery, but impaired NID response and lower reactive hyperaemia than controls. The preserved FMD and the comparable prevalence of carotid atherosclerosis indicate that CCHD patients have the same risk of atherosclerosis as controls.

Subclinical atherosclerosis in patients with cyanotic congenital heart disease.

INTRODUCTION: Survival in patients with cyanotic congenital heart disease (CCHD) has improved dramatically. The result is an ageing population with risk of acquired heart disease. Previous small uncontrolled studies suggested that these patients are protected against the development of atherosclerosis. To test this hypothesis, we sought to determine the prevalence of subclinical atherosclerosis in a larger population of patients with CCHD. METHOD: We compared the prevalence of subclinical atherosclerosis in adult CCHD patients from Denmark, Sweden, Norway and Australia, with that in age-, sex-, smoking status-, and body mass index matched controls. Coronary artery atherosclerosis was assessed on computed tomography with coronary artery calcification (CAC) score. Subclinical atherosclerosis was defined by CAC-score > 0. Carotid artery atherosclerosis was evaluated using ultrasound by measuring carotid plaque thickness (cPT-max) and carotid intima media thickness (CIMT). Lipid status was evaluated as an important atherosclerotic risk factor. RESULTS: Seventy-four patients with CCHD (57% women, median age 49.5 years) and 74 matched controls (57% women, median age 50.0 years) were included. There were no differences between the groups in: CAC-score > 0 (21% vs. 19%, respectively; p = 0.8), carotid plaques (19% vs. 9%, respectively; p = 0.1), cPT-max (2.3 mm vs. 2.8 mm, respectively; p = 0.1) or CIMT (0.61 mm vs. 0.61 mm, respectively; p = 0.98). And further no significant differences in lipoprotein concentrations measured by ultracentrifugation. CONCLUSION: Young adults with CCHD have similar cardiovascular risk factor profiles and measures of subclinical atherosclerosis, compared with controls. Given their increasing life expectancies, athero-preventive strategies should be an important part of their clinical management.

Arterial properties in adults with long-lasting active juvenile idiopathic arthritis compared to healthy controls.

BACKGROUND: The data on cardiovascular risk and systemic arterial properties in patients with long-lasting juvenile idiopathic arthritis (JIA) is limited. The objective of this study was to describe systemic arterial properties including characteristic impedance (Z0), total arterial compliance (C), and peripheral vascular resistance (R) in patients with long-lasting active JIA compared with matched controls, and to assess the relation to JIA disease variables and traditional cardiovascular risk factors. FINDINGS: Methods: Eighty-one JIA patients (median age 38.6) with at least 15 years of active disease were reexamined after median 29 years of disease duration and compared to 41 healthy controls. With use of echocardiography and calibrated right common carotid artery tonometric pulse traces, noninvasive estimates of pressure and blood flow from the aortic root were obtained and used to estimate the systemic arterial parameters Z0, C and R. RESULTS: The patients had higher Z0 as assessed by Windkessel model (mean ± SD 65.0 ± 30.1 versus 53.4 ± 18.8 10- 3 mmHg/ml/s, p = 0.027), lower C as assessed by either Windkessel model or ratio of stroke volume and pulse pressure (1.57 ± 0.46 versus 1.80 ± 0.65 ml/mmHg, p = 0.030, 1.29 ± 0.37 versus 1.43 ± 0.34 ml/mmHg, p = 0.038), and similar R compared to the controls. Years on daily prednisolone and insulin resistance were the most important correlates of Z0. Metotrexat use, polyarticular disease course and erythrocyte sedimentation rate were also associated with a higher Z0. CONCLUSION: Our results indicate that JIA patients had altered arterial properties as compared to controls. Years on daily prednisolone and insulin resistance were the most important correlates of altered arterial properties.

Epidemiological changes in Eisenmenger syndrome in the Nordic region in 1977-2012.

OBJECTIVE: Improved diagnostic tools, timely closure of the shunt and a better understanding of the complexity of Eisenmenger syndrome (ES) have led to improved care and treatment in tertiary centres. These may have decreased the incidence of ES and improved survival of patients with ES, although evidence is still lacking. The aim of this study was to investigate temporal changes in incidence, prevalence and mortality in patients with ES for 35 years in the Nordic region. METHODS: This was a retrospective population-based study including 714 patients with ES. Survival analysis was performed based on all-cause mortality and accounting for immortal time bias. RESULTS: The incidence of ES decreased from 2.5/million inhabitants/year in 1977 to 0.2/million inhabitants/year in 2012. Correspondingly, prevalence decreased from 24.6 to 11.9/million inhabitants. The median survival was 38.4 years, with 20-year, 40-year and 60-year survival of 72.5%, 48.4%, and 21.3%, respectively. Complex lesions and Down syndrome were independently associated with worse survival (HR 2.2, p<0.001 and HR 1.8, p<0.001, respectively). Age at death increased from 27.7 years in the period from 1977 to 1992, to 46.3 years from July 2006 to 2012 (p<0.001). CONCLUSIONS: The incidence and prevalence of ES in the Nordic region have decreased markedly during the last decades. Furthermore, the median age at death increased throughout the study period, indicating prolonged life expectancy in the ES population. However, increasing age represents decreased incidence, rather than improved survival. Nonetheless, longevity with ES is still shorter than in the background population.

Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction.

BACKGROUND: Chromogranin A is widely distributed throughout the neuroendocrine system and may, because of its long in vivo and in vitro half-life, be an attractive candidate for assessment of overall neuroendocrine activity. Recently, increased plasma levels of chromogranin A have been found in patients with chronic heart failure and related to the severity of symptoms and prognosis. The objective of the current study was to assess the prognostic value of chromogranin A levels after complicated myocardial infarction. METHODS: We assessed the association between plasma chromogranin A levels obtained in the hospitalization phase and time to hospitalization for heart failure or death in 217 patients with complicated myocardial infarction included in the OPTIMAAL trial. RESULTS: During a median follow-up time of 1017 days, there were 44 first events (30 deaths and 14 hospitalizations for congestive heart failure). Logarithmically transformed chromogranin A (P < .001) and N-terminal pro-B-type natriuretic peptide (P = .001), patient age (P < .001), estimated creatinine clearance (P < .001), a history of myocardial infarction or angina (P = .001), and diabetes mellitus (P = .011), using univariable Cox proportional hazards regression, were significantly associated with outcome, whereas sex, randomization status, history of hypertension, C-reactive protein, and the presence of inhospital heart failure were not. In a multivariable model, logarithmically transformed chromogranin A (P = .002), patient age (P < .0001), history of diabetes (P = .004), and male sex (P = .021) were independently predictive of outcome. CONCLUSION: Chromogranin A is a strong and independent prognostic indicator in patients with complicated myocardial infarction.

Elevated inflammatory markers in preeclamptic pregnancies, but no relation to systemic arterial stiffness.

OBJECTIVES: To investigate if circulating markers of systemic and vascular inflammation are associated with systemic arterial properties at term and 6months post-partum in women with preeclampsia (PE) and normal pregnancy (NP). STUDY DESIGN: Longitudinal, sampling at term and 6months post-partum in 34 women (32±6years) with PE and 61 women (32±5years) with NP. MAIN OUTCOME MEASURES: Circulating markers related to systemic and vascular inflammation were measured by enzyme immune-assay. Systemic arterial properties were estimated by Doppler (transthoracic echocardiography) and calibrated right subclavian artery pulse traces. RESULTS: CXCL16, soluble tumor necrosis factor receptor type 1 (sTNF-R1), monocyte chemoattractant peptide 1, pentraxin 3 and soluble vascular adhesion molecule 1 (sVCAM-1) were elevated at term in PE, and sTNF-R1 remained elevated 6months post partum compared to NP. However, apart from a negative correlation between mean arterial pressure and sTNF-R1 and sVCAM-1 at term, no associations between systemic and vascular inflammatory markers and systemic arterial properties as reflected by characteristic impedance and arterial elastance, representing proximal aortic stiffness and effective arterial elastance, were found at any time point. CONCLUSIONS: Preeclamptic pregnancies are characterized by increased circulating levels of systemic and vascular inflammatory markers. However, these are not associated with systemic arterial properties at term or 6months post partum.

Increased arterial stiffness in pre-eclamptic pregnancy at term and early and late postpartum: a combined echocardiographic and tonometric study.

BACKGROUND: Pre-eclampsia (PE) is characterized by hypertension and proteinuria, and complicates from 3%-10% of all pregnancies. The hemodynamic pathophysiology of the heart and systemic arteries in pre-eclamptic patients has not been well described. We therefore performed a comprehensive comparison of the systemic arterial properties at term and at 6 months postpartum in women with PE and in women with normal pregnancy (NP) and in nonpregnant women with a previous pre-eclamptic pregnancy (PPEP). METHODS: The comparison included 40 patients with PE, 40 others with a PPEP (at 3.5±1.0 years postpartum), and 65 women who had had an NP. Noninvasive estimates of blood flow and pressure in the aortic root were made with echocardiography and calibrated right subclavian artery pulse traces obtained through tonometry. Total arterial compliance (C), arterial elastance (Ea), characteristic impedance (Z0), and peripheral arterial resistance (R) were estimated both through the use of a three-element Windkessel model and Fourier analysis of pressure and flow data. RESULTS: At term, Z0, Ea, and R were higher by 37%, 25%, and 23%, respectively (all P < 0.05) in women with PE than in those with an NP, and C was lower by 12% (P < 0.05). The values of Z0, Ea, and R remained elevated at 6 months postpartum in women who had had PE, and were also elevated in those with a PPEP, as compared to their values in NP. CONCLUSIONS: Our results demonstrate that pre-eclamptic pregnancies are characterized by a higher resistance throughout the arterial system. The altered arterial properties (Ea, Z0, and R) persisted at 6 months after PE and were also elevated at 3 years postpartum in women with a PPEP, indicating that PE induces long-standing cardiovascular disturbances.

Changes in blood pressure during healthy pregnancy: a longitudinal cohort study.

OBJECTIVE: To study longitudinally changes in blood pressure (BP) and heart rate (HR) during healthy pregnancies and to evaluate the influence of parity, pregestational overweight, and excessive weight gain. METHODS: A prospective longitudinal cohort study of 57 healthy white women with singleton pregnancies. BP and HR were measured repeatedly at gestational age 14-16 weeks, 22-24 weeks, 30-32 weeks, 36 weeks, and 6 months postpartum using both an oscillometric measurement device (Dinamap) and finger arterial pressure (Finometer PRO). RESULTS: SBP, DBP, and mean arterial pressure (MAP) reached a statistically significant trough at gestational age 22-24 weeks using both measurement devices. When compared with the nonpregnant measurement, SBP at gestational age 22-24 weeks was 6.2 mmHg [95% confidence interval (95% CI) 1.3-11.2] lower measured by Finometer and 7.2 mmHg (95% CI 4.2-10.1) lower measured by Dinamap. DBP and MAP were 8.9 mmHg (95% CI 4.6-13.2) and 9.8 mmHg (95% CI 5.3-14.2) lower measured by Finometer. Measured by Dinamap, DBP and MAP were 4.5 mmHg (95% CI 1.7-7.3) and 5.4 mmHg (95% CI 2.8-7.9) lower at gestational age 22-24 weeks when compared with the nonpregnant state. SBP was significantly higher in women with pregestational BMI at least 25 kg/m with both measurement devices (both P < 0.05). There were no differences in SBP, DBP, or MAP depending on parity or excessive weight gain. CONCLUSION: BP measured repeatedly by two different noninvasive devices during pregnancy and postpartum showed a statistically significant drop in mid-pregnancy, followed by a progressive increase until term.