Symptoms during pregnancy in primiparous women with congenital heart disease.

Background: As more women with congenital heart disease (CHD) are reaching childbearing age, it becomes more common for their symptoms to be evaluated during pregnancy. However, pregnancy-related symptoms are similar to those caused by heart disease. This study investigated the prevalence of factors associated with symptoms during pregnancy in women with CHD. Methods: The national birth register was searched for primiparous women with CHD who were registered in the national quality register for patients with CHD. Results: Symptoms during the third trimester were reported in 104 of 465 evaluated women. The most common symptom was palpitations followed by dyspnea. Factors associated with symptoms were tested in a univariable model; higher NYHA classification (>1) (OR 11.3, 95%CI 5.5-23.2), low physical activity (≤3 h/week) (OR 2.1 95%CI 1.3-3.6) and educational level ≤ 12 years (OR 1.9 95%CI 1.2-3.0) were associated with having symptoms. In multivariable analysis, low physical activity level (OR 2.4 95%CI 1.2-5.0) and higher NYHA class (OR 11.3 95%CI 5.0-25.6) remained associated with symptoms during pregnancy. There were no cases with new onset of impaired systemic ventricular function during pregnancy. Conclusion: Symptoms during pregnancy are common in women with CHD but are often already present before pregnancy. Because ordinary symptoms during pregnancy often overlap with symptoms of heart disease, it is important to know if symptoms were present before pregnancy and if they became worse during pregnancy. These results should be included in pre-pregnancy counselling and considered in the monitoring during pregnancy.

Self-rated health in primiparous women with congenital heart disease before, during and after pregnancy - A register study.

Background. Poor maternal self-rated health in healthy women is associated with adverse neonatal outcomes, but knowledge about self-rated health in pregnant women with congenital heart disease (CHD) is sparse. This study, therefore, investigated self-rated health before, during, and after pregnancy in women with CHD and factors associated with poor self-rated health. Methods. The Swedish national registers for CHD and pregnancy were merged and searched for primiparous women with data on self-rated health; 600 primiparous women with CHD and 3062 women in matched controls. Analysis was performed using descriptive statistics, chi-square test and logistic regression. Results. Women with CHD equally often rated their health as poor as the controls before (15.5% vs. 15.8%, p = .88), during (29.8% vs. 26.8% p = .13), and after pregnancy (18.8% vs. 17.6% p = .46). None of the factors related to heart disease were associated with poor self-rated health. Instead, factors associated with poor self-rated health during pregnancy in women with CHD were ≤12 years of education (OR 1.7, 95%CI 1.2-2.4) and self-reported history of psychiatric illness (OR 12.6, 95%CI 1.4-3.4). After pregnancy, solely self-reported history of psychiatric illness (OR 5.2, 95%CI 1.1-3.0) was associated with poor self-rated health. Conclusion. Women with CHD reported poor self-rated health comparable to controls before, during, and after pregnancy, and factors related to heart disease were not associated with poor self-rated health. Knowledge about self-rated health may guide professionals in reproductive counselling for women with CHD. Further research is required on how pregnancy affects self-rated health for the group in a long-term perspective.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Adipokines are possible risk markers for aortic stenosis requiring surgery.

OBJECTIVES: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR). DESIGN: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents. RESULTS: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92-1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08-1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82-1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64-0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI). CONCLUSIONS: The adipokine leptin may promote the development of AS.

Pulmonary function in a cohort of heart-healthy individuals from Northern Sweden-a comparison with discordant reference values.

BACKGROUND: Dynamic spirometry is an important investigation to differentiate between impaired and normal lung function. This study aimed to evaluate the results of lung function testing in a cohort of subjects from Northern Sweden without any known heart or pulmonary disease. Our focus was to compare with two reference materials that have showed differences in the age-dependency of lung function in Swedish subjects. METHODS: The study population consisted of 285 healthy adults (148 males, 52%) between 20-90 years of age. The subjects had been randomly selected from the population register for inclusion in a study investigating cardiac function in heart-healthy subjects, but were also assessed with dynamic spirometry. At least seven percent reported smoking. Sixteen subjects presented with pulmonary functional impairments and were excluded from the current study. The sex-specific age-dependency in lung volumes was estimated using the LMS model, where non-linear equations were derived for the mean value (M), the location (L) or skewness, and the scatter (S) or coefficient of variation. This model of the observed lung function data was compared with reference values given by the original LMS model published by the Global Lung Initiative (GLI), and with the model from the recent Obstructive Lung Disease In Norrbotten (OLIN) study, where higher reference values were presented for Swedish subjects than those given by the GLI model. RESULTS: No differences were found in the age-dependency of pulmonary function between the LMS model developed in the study and the OLIN model. Although the study group included smokers, the original GLI reference values suggested significantly lower normal values of FEV1 (forced expiratory volume) and FVC (forced vital capacity), and consequently fewer subjects below the lower limit of normality, than both the rederived LMS and OLIN models. CONCLUSIONS: Our results are in line with previous reports and support that the original GLI reference values underestimate pulmonary function in the adult Swedish population. This underestimation could be reduced by updating the coefficients in the underlying LMS model based on a larger cohort of Swedish citizens than was available in this study.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.

BACKGROUND: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. METHODS: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0·0001], rush to toilet [p=0·0013], flatulence [p=0·0013], bowel cramp [p<0·0001], mucus [p=0·0014], blood in stool [p<0·0001], and limitation in daily activity [p=0·0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5·1% [95% CI -4·4 to 14·6]; p=0·38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5·7% [-3·8 to 15·2]; p=0·33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9·1% [-1·4 to 19·6]; p=0·15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5·0% [-5·0 to 15·0]; p=0·41). INTERPRETATION: Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

Phenotypes of adults with congenital heart disease around the globe: a cluster analysis.

OBJECTIVE: To derive cluster analysis-based groupings for adults with congenital heart disease (ACHD) when it comes to perceived health, psychological functioning, health behaviours and quality of life (QoL). METHODS: This study was part of a larger worldwide multicentre study called APPROACH-IS; a cross sectional study which recruited 4028 patients (2013-2015) from 15 participating countries. A hierarchical cluster analysis was performed using Ward's method in order to group patients with similar psychological characteristics, which were defined by taking into consideration the scores of the following tests: Sense Of Coherence, Health Behavior Scale (physical exercise score), Hospital Anxiety Depression Scale, Illness Perception Questionnaire, Satisfaction with Life Scale and the Visual Analogue Scale scores of the EQ-5D perceived health scale and a linear analogue scale (0-100) measuring QoL. RESULTS: 3768 patients with complete data were divided into 3 clusters. The first and second clusters represented 89.6% of patients in the analysis who reported a good health perception, QoL, psychological functioning and the greatest amount of exercise. Patients in the third cluster reported substantially lower scores in all PROs. This cluster was characterised by a significantly higher proportion of females, a higher average age the lowest education level, more complex forms of congenital heart disease and more medical comorbidities. CONCLUSIONS: This study suggests that certain demographic and clinical characteristics may be linked to less favourable health perception, quality of life, psychological functioning, and health behaviours in ACHD. This information may be used to improve psychosocial screening and the timely provision of psychosocial care.

Implantable cardiac devices in adult patients with repaired tetralogy of Fallot.

OBJECTIVES: Implantable cardiac devices are common in patients with tetralogy of Fallot (ToF) (18.3-21.3%) according to previous reports from large centres. We conducted this study to investigate the prevalence and incidence of cardiac devices in a less selected population of patients with ToF and assess factors other than arrhythmia associated with having a device. Design: 530 adult (≥18 years) patients with repaired ToF were identified in the national registry of congenital heart disease (SWEDCON) and matched with data from the Swedish pacemaker registry. Patients with implantable cardiac devices were compared with patients without devices. Results: Seventy-five patients (14.2%) had a device; 51 (9.6%) had a pacemaker and 24 (4.5%) had an implantable cardioverter defibrillator. The incidence in adult age (≥18 years) was 5.9/1000 patient years. Estimated device free survival was 97.5% at twenty, 87.2% at forty and 63.5% at sixty years of age. Compared with previous studies, the prevalence of devices was lower, especially for ICD. In multivariate logistic regression, cardiovascular medication (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8-6.8), impaired left ventricular function, (OR 2.6, 95%CI 1.3-5.0) and age (OR 1.02, 95%CI 1.002-1.05) were associated with having a device. Conclusion: The prevalence of devices in our population, representing a multicenter register cohort, was lower than previously reported, especially regarding ICD. This can be due to differences in treatment traditions with regard to ICD in this population, but it may also be that previous studies have reported selected patients with more severe disease.

Discontinuation of follow-up care for young people with complex chronic conditions: conceptual definitions and operational components.

BACKGROUND: A substantial proportion of young people with Complex Chronic Conditions (CCCs) experience some degree of discontinuation of follow-up care, which is an umbrella term to describe a broken chain of follow-up. Discontinuation of follow-up care is not clearly defined, and the great plethora of terms used within this field cannot go unnoticed. Terms such as "lost to follow-up", "lapses in care" and "care gaps", are frequently used in published literature, but differences between terms are unclear. Lack of uniformity greatly affects comparability of study findings. The aims of the present study were to (i) provide a systematic overview of terms and definitions used in literature describing discontinuation of follow-up care in young people with CCC's; (ii) to clarify operational components of discontinuation of follow-up care (iii); to develop conceptual definitions and suggested terms to be used; and (iv) to perform an expert-based evaluation of terms and conceptual definitions. METHODS: A systematic literature search performed in PubMed was used to provide an overview of current terms used in literature. Using a modified summative content analysis, operational components were analysed, and conceptual definitions were developed. These conceptual definitions were assessed by an expert panel using a survey. RESULTS: In total, 47 terms and definitions were retrieved, and a core set of operational components was identified. Three main types of discontinuation of follow-up care emerged from the analysis and expert evaluation, conceptually defined as follows: Lost to follow-up care: "No visit within a defined time period and within a defined context, and the patient is currently no longer engaged in follow-up care"; Gap in follow-up care: "Exceeded time interval between clinic visits within a defined context, and the patient is currently engaged in follow-up care"; and Untraceability: "Failure to make contact due to lack of contact information". CONCLUSION: By creating a common vocabulary for discontinuation of follow-up care, the quality of future studies could improve. The conceptual definitions and operational components provide guidance to both researchers and healthcare professionals focusing on discontinuation of follow-up care for young people with CCCs.

Prevalence of fatigue in adults with congenital heart disease.

AIMS: The aim of this cross-sectional study was to examine the prevalence of the multidimensional phenomenon of fatigue in adults with congenital heart disease. BACKGROUND: Adults with congenital heart disease are a growing population, and patient-reported outcomes can provide valuable information about the patient's experience of living with CHD. Fatigue is a multidimensional phenomenon that can be described as an overwhelming feeling of exhaustion with a reduced capacity of mental and physical work. Fatigue can be observed clinically in adults with congenital heart disease, but the actual prevalence is unknown. METHODS: Fatigue was assessed by the Multidimensional Fatigue Inventory which enables the respondent to report the presence of fatigue according to five dimensions: "general fatigue," "physical fatigue," "mental fatigue," "reduced motivation," and "reduced activity." The questionnaire was sent to 463 patients in Lund and Umeå. Four groups with complex CHD and two groups with moderately complex CHD were included. The reliability (internal consistency) of the Multidimensional Fatigue Inventory was tested for all dimensions and groups of diagnosis. RESULTS: The response rate was 56.6% (n= 262). In patients with complex CHD, 40.0-59.4% reported severe to very severe general fatigue, and patients with a single ventricle reported the highest prevalence (59.4%). Among patients with complex CHD, 29.2-40.0% reported severe to very severe mental fatigue. The Multidimensional Fatigue Inventory had a high reliability measured with Cronbach's alpha. CONCLUSIONS: The study findings show a relatively high prevalence of fatigue in adults with congenital heart disease, and general fatigue was the most prevalent. Further studies are needed regarding fatigue and its causes and consequences in adults with congenital heart disease. RELEVANCE TO CLINICAL PRACTICE: The Multidimensional Fatigue Inventory proved to be an instrument with high reliability and low internal loss, which suggests that the instrument may be suitable to use as a patient-reported outcome in the care of adults with congenital heart disease, preferably at repeated occasions.

Despite reductions in muscle mass and muscle strength in adults with CHD, the muscle strength per muscle mass relationship does not differ from controls.

BACKGROUND: Patients with CHD exhibit reduced isometric muscle strength and muscle mass; however, little is known how these parameters relate. Therefore, the aim was to investigate the relation between isometric limb muscle strength and muscle mass for patients in comparison to age- and sex-matched control subjects. METHODS: Seventy-four patients (35.6 ± 14.3 years, women n = 22) and 74 matched controls were included. Isometric muscle strength in elbow flexion, knee extension, and hand grip was assessed using dynamometers. Lean mass, reflecting skeletal muscle mass, in the arms and legs was assessed with dual-energy x-ray absorptiometry. RESULTS: Compared to controls, patients had lower muscle strength in elbow flexion, knee extension, and hand grip, and lower muscle mass in the arms (6.6 ± 1.8 kg versus 5.8 ± 1.7 kg, p < 0.001) and legs (18.4 ± 3.5 kg versus 15.9 ± 3.2 kg, p < 0.001). There was no difference in achieved muscle force per unit muscle mass in patients compared to controls (elbow flexion 0.03 ± 0.004 versus 0.03 ± 0.005 N/g, p = 0.5; grip strength 0.008 ± 0.001 versus 0.008 ± 0.001 N/g, p = 0.7; knee extension 0.027 ± 0.06 versus 0.028 ± 0.06 N/g, p = 0.5). For both groups, muscle mass in the arms correlated strongly with muscle strength in elbow flexion (patients r = 0.86, controls, r = 0.89), hand grip (patients, r = 0.84, controls, r = 0.81), and muscle mass in the leg to knee extension (patients r = 0.64, controls r = 0.68). CONCLUSION: The relationship between isometric muscle strength and limb muscle mass in adults with CHD indicates that the skeletal muscles have the same efficiency as in healthy controls.

High prevalence of ascending aortic dilation in adults with repaired coarctation of the aorta.

BACKGROUND: Ascending aortic dilation is a feared complication in adults with repaired coarctation of the aorta, as the condition is associated with life-threatening complications such as aortic dissection and rupture. However, the data are currently limited regarding factors associated with ascending aortic dilation in these patients. METHODS AND RESULTS: From the national register of congenital heart disease, 165 adult patients (≥ 18 years old) with repaired coarctation of the aorta, and echocardiographic data on aortic dimensions, were identified (61.2% male, mean age 35.8 ± 14.5 years). Aortic dilation (aortic diameters > 2 SD above reference mean) was found in 55 (33.3%) of the 165 included patients, and was associated with manifest aortic valve disease in univariable logistic regression analysis (OR 2.44, 95% CI [1.23, 4.83]). CONCLUSIONS: Aortic dilation is common post-repair of coarctation of the aorta, and is associated with manifest aortic valve disease and thus indirectly with the presence of a bicuspid aortic valve. However, no association was found between aortic dilation and age or blood pressure.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.

BACKGROUND: Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation. METHODS: In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1-7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758-1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity. INTERPRETATION: Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

Effect of medical treatment in patients with systemic right ventricle.

Objective: Congenitally corrected and surgical atrial redirected transposition of the great arteries (TGA) represents states where the morphological right ventricle serves as a systemic ventricle (S-RV). The S-RV is prone to failure, but data on medical treatment on this problem is limited. The purpose of this study was to evaluate the survival in adults with S-RV, with or without heart failure treatment. Design: The SWEDCON registry was used to collect data. All adults with S-RV and minimum follow-up of 1 year were included retrospectively. Medical treatment was defined as taking beta-blockers and/or ACE inhibitors and/or ARBs for more than 50% of the time. Results: We identified 343 patients with S-RV (median age: 21 years). Surgical atrial redirected TGA was present in 58% and congenitally corrected TGA in 42% of patients. The medically treated group (n = 126) had higher rates of impaired S-RV function, use of diuretics, pacemaker and higher NYHA functional class at baseline compared to controls. The proportion of patients with impaired functional class did not change over time in the medically treated group, but increased in controls (21% vs. 30%, p = .015). In Kaplan-Meier analysis, the mean follow-up was 10.3 years, no difference in survival was seen between the groups. Conclusions: Medical treatment may be beneficial in patients with S-RV and impaired functional class and appears to be safe in the long term. The treatment group had equal survival to controls, despite worse baseline characteristics, which might be a result of slower progression of disease in this group.

Healthcare system inputs and patient-reported outcomes: a study in adults with congenital heart defect from 15 countries.

BACKGROUND: The relationship between healthcare system inputs (e.g., human resources and infrastructure) and mortality has been extensively studied. However, the association between healthcare system inputs and patient-reported outcomes remains unclear. Hence, we explored the predictive value of human resources and infrastructures of the countries' healthcare system on patient-reported outcomes in adults with congenital heart disease. METHODS: This cross-sectional study included 3588 patients with congenital heart disease (median age = 31y; IQR = 16.0; 52% women; 26% simple, 49% moderate, and 25% complex defects) from 15 countries. The following patient-reported outcomes were measured: perceived physical and mental health, psychological distress, health behaviors, and quality of life. The assessed inputs of the healthcare system were: (i) human resources (i.e., density of physicians and nurses, both per 1000 people) and (ii) infrastructure (i.e., density of hospital beds per 10,000 people). Univariable, multivariable, and sensitivity analyses using general linear mixed models were conducted, adjusting for patient-specific variables and unmeasured country differences. RESULTS: Sensitivity analyses showed that higher density of physicians was significantly associated with better self-reported physical and mental health, less psychological distress, and better quality of life. A greater number of nurses was significantly associated with better self-reported physical health, less psychological distress, and less risky health behavior. No associations between a higher density of hospital beds and patient-reported outcomes were observed. CONCLUSIONS: This explorative study suggests that density of human resources for health, measured on country level, are associated with patient-reported outcomes in adults with congenital heart disease. More research needs to be conducted before firm conclusions about the relationships observed can be drawn. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02150603. Registered 30 May 2014.

Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.

BACKGROUND: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. METHODS: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. RESULTS: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. CONCLUSIONS: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Arterial hypertension and diastolic blood pressure associate with aortic stenosis.

OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age. DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking. RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]). CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis.

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFRcystatin C and eGFRcreatinine and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFRcystatin C and eGFRcreatinine. A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFRcystatin C and eGFRcreatinine was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

Aortic stiffness in families with inherited non-syndromic thoracic aortic disease.

BACKGROUND: In families with an inherited form of non-syndromic thoracic aortic disease (TAAD), aortic diameter alone is not a reliable marker for disease occurrence or progression. To identify other parameters of aortic function, we studied aortic stiffness in families with TAAD. We also compared diameter measurements obtained by transthoracic echocardiography (TTE) and magnetic resonance imaging (MRI). METHODS: Seven families, including 116 individuals, with non-syndromic TAAD, were studied. The aortic diameter was measured by TTE and MRI. Aortic stiffness was assessed as local distensibility in the ascending aorta and as regional and global pulse wave velocity (PWV). Individuals with a dilated thoracic aorta (n = 21) were compared with those without aortic dilatation (n = 95). RESULTS: Ascending aortic diameter measured by TTE strongly correlated with the diameter measured by MRI (r2 = 0.93). The individuals with dilated aortas were older than those without dilatation (49 vs 37 years old). Ascending aortic diameter increased and distensibility decreased with increasing age; while, PWV increased with age and diameter. Some young subjects without aortic dilatation showed increased aortic stiffness. Individuals with a dilated thoracic aorta had significantly higher PWV and lower distensibility, measured by MRI than individuals without dilatation. CONCLUSIONS: Diameters measured with TTE agree with those measured by MRI. Aortic stiffness might be a complementary marker for aortic disease and progression when used with aortic diameter, especially in young individuals.

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.