Psychiatric morbidity and work participation in patients with congenital ventricular septal defects: a case-controlled study.

BACKGROUND: The burden of psychiatric morbidity, level of education, and work participation is currently unknown in patients with congenital ventricular septal defects (VSD). METHODS: In a Danish population-based cohort study using nationwide medical registries the burden of psychiatric disorders, use of psychotropic agents, level of education, and work participation were examined in patients with isolated congenital VSD and controls from the general population matched by age and sex. Subjects with known chromosomal abnormalities were excluded. To compute estimates, Cox proportional regression model, Fine and Gray's competing risk regression, and Kaplan-Meier failure function were used. RESULTS: We included 8 006 patients and 79 568 controls born before 2018. Median follow-up was 23 years. Compared with controls, patients with VSD displayed a HR of 1.24 (95% CI: 1.17-1.32) for any psychiatric disorder where the hazard for intellectual disabilities was most pronounced [HR of 3.66 (95% CI: 2.98-4.50)]. The use of psychotropic agents was higher in patients compared with controls [HR 1.14 (95% CI: 1.09-1.20)]. The work participation was lower in patients with VSD compared with controls (P < 0.001) and was lower in patients with VSD with a psychiatric disorder compared with those without (P < 0.001). The 40-year cumulative incidence of permanent social security benefits was 29% in patients with psychiatric disorders (versus 21% in controls with psychiatric disorders) and 8% in patients without psychiatric disorders (versus 4% in controls). CONCLUSION: Patients with isolated VSD suffer from a higher burden of psychiatric disorders and display lower work participation compared with matched controls from the general Danish population. It is important to consider longer-term impacts on mental health, education, and subsequent employment in patients with VSD, in addition to cardiovascular effects, as these factors severely affect quality of life and have direct socioeconomic implications on an individual and societal level.

Risk of permanent social security benefits and overview of work participation among patients with obstructive sleep apnea.

BACKGROUND: In this nationwide study, we used Danish population registries to estimate the excess risk of receiving permanent social security benefits for patients with obstructive sleep apnea (OSA) and to track their labour force participation. METHODS: We identified all Danish citizens receiving a diagnosis of OSA between 1995 and 2015. As a reference cohort, we randomly selected 10 citizens for each patient, matched by sex and birth year. Using the Fine and Gray competing risk regression, we estimated the cumulative incidences of receiving permanent social security benefits. Cox proportional hazard models were used to compare the risk of receiving permanent social security benefits in patients with OSA compared to the reference cohort. The Danish Rational Economic Agents' Model (DREAM) database was used to identify the labour market status prior to diagnosis, at time of diagnosis, and after diagnosis. RESULTS: We identified 48,168 patients with OSA. A total of 12,413 (25.8%) patients with OSA had received permanent social security benefits, compared with 75,812 (15.7%) individuals in the reference cohort. Patients with OSA had a significantly increased risk of receiving permanent social security benefits when compared with the reference cohort (hazard ratio, 1.95; 95% CI, 1.88-2.02; and subhazard ratio, 1.92; 95% CI, 1.85-1.98). Work participation was lower for OSA patients compared to references at all time-points. CONCLUSION: Patients with OSA have a moderately increased risk of receiving permanent social security benefits in Denmark after controlling for available confounders.

School performance is impaired in children with both simple and complex congenital heart disease.

Background: We do not know if children born with a simple or uncorrected congenital heart disease (CHD) have school performance issues and an increased need for special education compared to healthy peers. With this study we examine the school performance and the need for special education in children with both simple and complex CHD. Further, we evaluate if exposure to preeclampsia or smoking affects the need for special education. Methods: In this nation-wide population based registry study, we included all Danish children with CHD born 1994-2012. In addition ten age and gender matched control per CHD child were included. Non-singletons and children born with a syndrome were excluded. Exposure was defined as having a CHD and the outcome was defined as needing special education service in the Danish primary and lower secondary school. Results: The population consisted of 7,559 CHD children and 77,046 non-CHD children (controls). CHD children had a higher need for special education compared to non-CHD children, OR: 2.14 (95% CI: 2.00; 2.28), p < 0.001. The odds ratio was also increased when comparing children with a minor CHD to non-CHD children, OR: 1.99 (95% CI: 1.86; 2.14), p < 0.001. CHD children exposed to preeclampsia or smoking had a higher risk of receiving special education compared to unexposed CHD children. Conclusion: We find that school performance is impaired in children born with CHD. This applies to both simple and complex CHD. If a child with CHD was exposed to preeclampsia or maternal smoking this further increased the need for special education.

Lifetime Burden of Morbidity in Patients With Isolated Congenital Ventricular Septal Defect.

Background The lifetime burden of morbidity in patients with isolated congenital ventricular septal defect (VSD) is not completely described. Methods and Results In a population-based cohort study in Denmark using nationwide medical registries, we included 8006 patients diagnosed with a congenital VSD before 2018 along with 79 568 randomly selected controls from the general Danish population matched by birth year and sex. Concomitant congenital cardiac malformations and chromosomal abnormalities were excluded. Cox proportional hazard regression, Fine and Gray competing risk regression, and Kaplan-Meier survival function were used to estimate burden of morbidity, compared with matched controls. Median follow-up was 23 years (interquartile range, 11-37 years). The hazard ratio (HR) of heart failure was high in both patients with unrepaired and surgically closed VSD when compared with their corresponding matched controls (5.4 [95% CI, 4.6-6.3] and 30.5 [95% CI, 21.8-42.7], respectively). Truncated analyses with time from birth until 1 year after VSD diagnosis (unrepaired) or surgery (surgically closed) censored revealed reduced but persisting late hazard of heart failure. Similarly, the late hazard of arrhythmias and pulmonary arterial hypertension was high irrespective of defect closure. The HR of endocarditis was 28.0 (95% CI, 19.2-40.9) in patients with unrepaired defect and 82.7 (95% CI, 37.5-183.2) in patients with surgically closed defect. The increased HR diminished after VSD surgery. In general, the incidence of morbidity among patients with unrepaired VSD accelerated after the age of 40 years. Conclusions Patients with isolated congenital VSD carry a substantial burden of cardiovascular morbidity throughout life, irrespective of defect closure.

Survival of patients with congenital ventricular septal defect.

AIMS: The long-term survival of patients with isolated congenital ventricular septal defect (VSD) is not well described. The aim of this study was to describe the survival of a national cohort of patients with VSD compared with the general population. METHODS AND RESULTS: Using Danish nationwide medical registries, all patients diagnosed with congenital VSD (n = 9,136) in the period 1977-2018 were included. Patients with chromosomal abnormalities and concomitant congenital cardiac malformations other than atrial septal defect were excluded. Each patient was matched by birthyear and sex with ten controls from the general Danish population. Kaplan-Meier survival function and Cox proportional hazard regression were used to compute survival and mortality risk. Median follow-up was 22 years (interquartile range: 11-37). VSD patients displayed lower survival (P<0.001) yielding a hazard ratio (HR) for mortality of 2.7 [95% confidence interval (CI): 2.4-3.0] compared with matched controls. The adjusted HR for mortality among patients with unrepaired VSD was 2.7 (95% CI: 2.4-3.0) and 2.8 (95% CI: 2.1-3.7) for patients with surgically closed VSD. Stratified by era of VSD diagnosis, the HR for mortality was 3.2 (95% CI: 2.8-3.7) for unrepaired patients diagnosed before 1990 and 2.4 (95% CI: 2.0-2.7) for patients diagnosed later. Cardiac-related death was the commonest cause of death among unrepaired (30%) and surgically closed (65%) patients. CONCLUSION: Patients with VSD had lower survival compared with the general population. The HR for mortality was increased over 2.5-fold in patients with unrepaired defect (Eisenmenger syndrome excluded) and over 1.5-fold in patients with surgically closed defect (excluding surgical mortality).

Increased inflammatory markers in adult patients born with an atrial septal defect.

Patients with atrial septal defect (ASD) have higher mortality and higher risk of atrial fibrillation, heart failure, pneumonia, and stroke than the general population even if the ASD closes spontaneously in childhood. The reason for the long-term complications remains unknown. Since many of the complications can be linked up with alterations in inflammatory response, we speculate that inflammation may contribute to the association between ASD and morbidity and mortality. We investigated inflammatory activity in adults with an ASD compared with controls. We included 126 adults with an unrepaired ASD. A group of healthy controls were recruited as comparison group (n = 23). Serum samples were analyzed for 92 inflammation-related protein biomarkers using a proximity extension assay. A pathway enrichment analysis was performed using Reactome database. Out of 92 biomarkers, 73 were eligible for data analysis. Increased levels of 14 (19%) biomarkers were found in patients with open ASD and 24 (33%) biomarkers in patients with spontaneously closed defects compared with controls (p < 0.05). Multiple inflammatory pathways showed stronger enrichment in both patient groups when compared with controls. In conclusion, inflammatory activity is altered in adult patients with an unrepaired ASD compared with healthy controls. The increased inflammatory burden of patients with an unrepaired ASD may contribute to the development of morbidities.

Pre-eclampsia is associated with increased neurodevelopmental disorders in children with congenital heart disease.

Aims: Our primary aim was to examine whether exposure to pre-eclampsia increases the risk of neurodevelopmental disorders in children born with congenital heart disease (CHD). Our secondary aim was to evaluate whether CHD and pre-eclampsia may act in synergy and potentiate this risk. Method and results: Using population-based registries, we included all Danish children born with CHD between 1994 and 2017. Non-singletons and children born with a syndrome were excluded. Neurodevelopmental disorders including attention-deficit/hyperactivity disorder, autism spectrum disorders, and tic disorders were identified with the use of the 10th edition of International Classification of Disease (ICD-10) codes DF80-DF98. Using Cox proportional hazard regression, we estimated the risk of neurodevelopmental disorders in children with CHD exposed to pre-eclampsia compared with those with CHD not exposed to pre-eclampsia. The population consisted of 11 449 children born with CHD. Children exposed to pre-eclampsia had an increased risk of neurodevelopmental disorders, hazard ratio: 1.84 (95% confidence interval: 1.39-2.42). Furthermore, a comparison cohort of 113 713 children with no CHD diagnoses were included. Using cumulative incidence analyses with death as competing risk, we compared the risk of neurodevelopmental disorders if exposed to pre-eclampsia among children with CHD and children without CHD. Exposure to pre-eclampsia drastically increased the cumulative incidence of neurodevelopmental disorders in children born with CHD. Conclusion: Exposure to pre-eclampsia is associated with increased risk of neurodevelopmental disorders in children born with CHD. CHD and pre-eclampsia may act in synergy and potentiate this effect. Clinicians should therefore be especially attentive to neurodevelopmental problems in this vulnerable subgroup.

Comparison of Outcome in Patients With Familial Versus Spontaneous Atrial Septal Defect.

Patients with atrial septal defects (ASDs) have increased mortality and morbidity. This can only partly be explained by hemodynamic changes caused by the ASD, suggesting additional underlying causes. Patients with an ASD have an increased burden of pathogenic gene variants in ASD-related genes, indicating genetics as an important factor in etiology. Inheritance of genetic variants with high impact can cause ASD in relatives (familial ASD). This study aimed to investigate whether lifelong outcomes were different in patients with familial ASD compared with patients with sporadic ASD. We used health registries and a nationwide cohort of 2,151 patients with ASD to compare the incidences of atrial fibrillation or flutter (together abbreviated as AF), heart failure, and mortality between patients with familial and sporadic ASD using Cox proportional hazard ratio and Fine and Gray analysis. Patients with familial ASD experienced AF and heart failure earlier in life than patients with sporadic ASD, with hazard ratios of 1.6 and 1.7, respectively. Subdistribution hazard ratios showed an increased risk of AF and heart failure in patients with familial ASD compared with patients with sporadic ASDs (2.3 and 3.1, respectively). Our results suggest that genetic variants with high impact may influence the outcomes of patients with ASD. In conclusion, patients with familial ASD have an increased risk and an earlier onset of AF and heart failure compared with patients with sporadic ASD, hence clinical awareness of arrhythmias and heart failure in patients with familial ASD may lead to timely treatment.

Risk of Lifetime Psychiatric Morbidity in Adults With Atrial Septal Defect (from a Nation-Wide Cohort).

In this nation-wide cohort study we report the first long-term results of the association between having a atrial septal defects (ASD) on psychiatric disorders and use of psychotropic agents. Through population-based registries we included Danish individuals born before 1994 who received an ASD diagnosis between 1959and 2013. We used Cox proportional hazards regression and Fine and Grey competing risk regression to estimate the risk of receiving a psychiatric diagnosis and use of psychotropic medicine compared with a gender and age matched background population cohort. In 2,277 patients with a median follow-up from ASD diagnosis of 23.4 years (range 0.2 to 59.3 years) we found ASD patients to have a higher risk of psychiatric disorders (adjusted hazard ratio [HR]: 3.9; 95% confidence interval [CI] 3.4 to 4.5) compared with the comparison cohort and a cumulative incidence of using psychotropic agents 30 years after the ASD diagnosis of 47.4% (95% CI: 40.3 to 55.1) in the ASD patients and 25.5%, (95% CI: 23.5 to 27.8) in the comparison cohort. Diagnosis of the ASD before the age of 15 years (adjusted HR: 3.4; 95% confidence interval: 2.0 to 4.0) and surgical correction of the defect (HR: 1.5 (95% CI: 1.2 to 1.8), p <0.0001) had a higher risk than those with an ASD diagnosis after the age of 15 years and those with transcatheter closure of the defect. In conclusion, ASD patients had increased long-term risk of psychiatric disorder and use of psychotropic agents compared with a gender and age matched general population controls.

Pacemaker and conduction disturbances in patients with atrial septal defect.

OBJECTIVE: To determine the prevalence of pacemaker and conduction disturbances in patients with atrial septal defects. DESIGN: All patients with an atrial septal defect born before 1994 were identified in the Danish National Patient Registry, and 297 patients were analysed for atrioventricular block, bradycardia, right bundle branch block, left anterior fascicular block, left posterior fascicular block, pacemaker, and mortality. Our results were compared with pre-existing data from a healthy background population. Further, outcomes were compared between patients with open atrial septal defects and atrial septal defects closed by surgery or transcatheter. RESULTS: Most frequent findings were incomplete right bundle branch block (40.1%), left anterior fascicular block (3.7%), atrioventricular block (3.7%), and pacemaker (3.7%). Average age at pacemaker implantation was 32 years. Patients with defects closed surgically or by transcatheter had an increased prevalence of atrioventricular block (p < 0.01), incomplete right bundle branch block (p < 0.01), and left anterior fascicular block (p = 0.02) when compared to patients with unclosed atrial septal defects. At age above 25 years, there was a considerably higher prevalence of atrioventricular block (9.4% versus 0.1%) and complete right bundle branch block (1.9% versus 0.4%) when compared to the background cohorts. CONCLUSIONS: Patients with atrial septal defects have a considerably higher prevalence of conduction abnormalities when compared to the background population. Patients with surgically or transcatheter closed atrial septal defects demonstrated a higher demand for pacemaker and a higher prevalence of atrioventricular block, incomplete right bundle branch block, and left anterior fascicular block when compared to patients with unclosed atrial septal defects.

Congenital Heart Disease and Risk of Suicide and Self-Harm: A Danish Nationwide Cohort Study.

Background In this nationwide study, we used the unique Danish registries to estimate the risk of suicide and deliberate self-harm in patients with congenital heart disease (CHD). Methods and Results We identified all Danish citizens receiving a diagnosis of CHD between 1977 and 2007. As a reference cohort, we randomly selected 10 citizens for each patient, matched by sex and birth year. Using the Fine and Gray competing risk regression, we estimated the cumulative incidences of suicide and self-harm, and Cox proportional regression analysis was used to compare the risk of suicide and deliberate self-harm in patients with CHD with the reference cohort. We identified 14 433 patients with CHD. Mean follow-up was 21.3 years, with a maximum follow-up of 42 years. Since the time of diagnosis, 2659 patients had died, with a median age of death of 23 years. A total of 15 patients had died by suicide, compared with 232 suicides in the reference cohort. Patients with CHD had a low and similar risk of dying by suicide when compared with the reference cohort (cause-specific hazard ratio, 0.81; 95% CI, 0.48-1.37; and subhazard ratio, 0.68; 95% CI, 0.41-1.16). We identified 336 events of self-harm among patients with CHD, and 3484 events in the reference group. The overall risk of deliberate self-harm was not increased in patients with CHD when compared with the reference group (subhazard ratio, 0.95; 95% CI, 0.85-1.06). Conclusions This is the first study to estimate the risk of suicide and deliberate self-harm in patients with CHD. We found that patients with CHD do not have an increased risk of suicide or deliberate self-harm when compared with a large reference cohort.

Pregnancy outcome in women with atrial septal defect: associated with in vitro fertilisation and pre-eclampsia.

Objective: To investigate in vitro fertilisation (IVF) in women with atrial septal defect (ASD), and to examine the maternal characteristics and outcome of pregnancy, as well as the fetal outcome of infants born by women with ASD. Methods: We used population-based registries in this nationwide cohort study, including Danish individuals born before 1994 who received an ASD diagnosis between 1959 and 2014. Patients were compared with a random reference sample (ratio of 10 citizens per patient) matched by sex and age. The Danish Medical Birth Register (DMBR) contains data on all pregnancies and births in Denmark from 1977 to present. Risk of IVF treatment as well as maternal, pregnancy and fetal outcomes were compared. Results: A total of 2277 Danish patients had a validated ASD diagnosis. Of these, 310 women were identified in the DMBR. Women with ASD had an increased risk of receiving IVF treatment (HR 3.14, 95% CI 2.1 to 4.7, p<0.0001), and a higher proportion of patients received IVF treatment when compared with the reference cohort (10.6% vs 3.2%; p<0.001). Furthermore, patients had more multiple births. Looking at singleton pregnancies (n=519), pre-eclampsia occurred more frequently in patients with ASD during pregnancy (6.7% vs 2.3%; p<0.001). Infants from mothers with ASD were found to have perinatal outcomes comparable to those of infants from the reference group. Conclusion: Women with ASD had an increased risk of and received more IVF treatment than the reference group. The outcome of pregnancy in these patients were generally uneventful, however, we did confirm that pre-eclampsia occurred more frequently.

Effect of Atrial Septal Defect in Adults on Work Participation (from a Nation Wide Register-Based Follow-Up Study Regarding Work Participation and Use of Permanent Social Security Benefits).

Low work participation is well known in patients with chronic disease but has not been described in patients with atrial septal defect (ASD). In this nation-wide cohort study, we report the first long-term follow-up of use of permanent social security benefits and work participation in adults with ASD. All Danes born before 1994 and diagnosed with ASD from 1959 to 2013 (n = 2,277) were identified from the Danish medical registries. We used Cox proportional hazards regression to compare the risk of receiving permanent social security benefits in the ASD patients compared with an age- and gender-matched general population cohort. Using the DREAM database, we calculated work participation score and proportion of patients working or not working at the age of 30 years. Median follow-up from ASD diagnosis was 23.4 years (range 0.2 to 59.3). ASD patients had a higher risk of receiving permanent social security benefits (hazard ratio 2.3 [95% confidence interval 2.1 to 2.6]) compared with the comparison cohort with 24% of the ASD patients receiving permanent social security benefits at the end of follow-up compared with 12% of the comparison cohort. At the age of 30 years, the proportion not working was 28% in the ASD cohort and 18% in the comparison cohort. In patients with ASD, 23% of those without a job had a psychiatric diagnosis. In conclusion, the risk of receiving permanent social security benefits was twice as high in patients with ASD and the work participation score was reduced compared with the background population.

Hidden burden of arrhythmias in patients with small atrial septal defects: a nationwide study.

Background: In recent Danish nationwide register-based study, adults with small, unrepaired atrial septal defects (ASD) have increased risk of pneumonia, atrial fibrillation (AF) and stroke. Moreover, they revealed higher mortality than the background population. Objective: In this nationwide study, we evaluate the hidden burden of atrial and ventricular arrhythmias in adult patients with a small, unrepaired ASD without a previous diagnosis of AF. Methods: All Danish patients, aged 18-65, diagnosed between 1953 and 2011 with an unrepaired ASD and no documented AF were invited for 7 days Holter-recording, echocardiography and 6 min walk test. The first 48 hours Holter-recording was completely analysed, while only AF was screened for throughout all 7 days. Furthermore, the entire patient group were characterised using the unique Danish registries. Results: A total of 151 patients (mean age 32 years) were included. Approximately 80% of the patients had spontaneous closure of their defect. Despite this, occult arrhythmias were frequent. The most common arrhythmia was supraventricular tachycardia (n=24, 16%) with non-sustained atrial arrhythmias in 21 patients and AF in two patients. A considerable number of patients had non-sustained ventricular tachycardia (n=12, 8%). Patients with ASD and tachyarrhythmias had increased right ventricular to left ventricular diastolic area in echocardiography and higher age when compared with ASD patients without arrhythmias. Conclusion: Adult patients with small, unrepaired ASD have a hidden burden of both atrial and ventricular tachyarrhythmias. The mechanism likely relates to the residua of previous right-heart volume overload and incomplete reverse remodelling. Our results support guidelines recommending continued follow-up of patients with small, unrepaired ASD.

Small atrial septal defects are associated with psychiatric diagnoses, emotional distress, and lower educational levels.

OBJECTIVE: For the first time, we wish to assess the psychiatric burden in adult patients living with small, unrepaired atrial septal defects (ASD) using register-based data, combined with self-reported measures on levels emotional distress and educational status. DESIGN: A descriptive study using both the unique Danish registries and validated psychiatric questionnaires and scales, including: The Symptom Checklist, Whiteley-7, and Brief Illness Perception Questionnaire. PATIENTS: Adult patients with small, unrepaired ASD, diagnosed between 1953 and 2011. OUTCOME MEASURES: Number of register-based psychiatric diagnoses. Additionally, symptoms of anxiety, depression, somatization, health anxiety, illness perception, and levels of educational attainment compared to age- and gender-matched individuals from the reference group. RESULTS: We identified 723 Danish patients with a small, unrepaired ASD. Approximately 17% of the patients eligible for inclusion had one or more psychiatric diagnoses. The most common diagnoses were neurotic, stress-related, and somatoform disorders. A total of 140 patients (mean age 33 years) was included for examination of their mental health using psychiatric questionnaires and scales. Patients with small ASD had higher scores of depression and anxiety when compared to the reference group (0.57 ± 0.67 vs 0.39 ± 0.52; P < .001). Furthermore, patients reported more symptoms of somatization (0.51 ± 0.48 vs 0.34 ± 0.39; P < .001). Finally, a higher percentage of patients with an unrepaired ASD had no education beyond high school when compared to the reference group (33.3% vs 14.3%; P < .001) and a smaller proportion of patients had completed a short-cycle higher education (6.5% vs 16.1%; P = .002). CONCLUSION: Patients with a small, unrepaired ASD in adult life have more symptoms of anxiety, depression, and somatization compared to the reference group. Furthermore, fewer patients had no education beyond high school. These results support the guidelines that adults with small ASD warrants regular lifelong follow-up in specialized clinics aware of not only adverse somatic outcome but also rates of depression and anxiety.

The Burden of Migraine in Adults with Atrial Septal Defect: A Nationwide Cohort Study.

We aimed to investigate migraine diagnoses in a hospital setting, use of prescription migraine medicine and levels of serotonin in patients with atrial septal defect. Using Danish national registries to identify all patients born before 1994 diagnosed with atrial septal defect between 1959 and 2013, thus including 2277 patients and a gender and age matched comparison cohort of 22756. Plasma serotonin was measured in 136 patients with a small, unclosed, atrial septal defects and 18 controls. Patients with atrial septal defect had an increased risk of receiving a migraine diagnosis (HR 3.4 (95% CI: 2.6-4.6)) and receiving migraine medicine (HR 1.8 (95% CI: 1.2-2.5)). Ten years after closure, 93% of those using migraine medicine pre-closure, were still receiving this. The risk of having very high plasma serotonin levels was increased in patients with atrial septal defect compared with the control group, but there was no difference in the median values between the two groups. Migraine and use of migraine medicine were increased in atrial septal defect patients. The use of medicine was not diminished by closure of the defect. Plasma serotonin was severely elevated in 18% of the patients with atrial septal defect.

Biventricular contractility during exercise in adults with small, unrepaired atrial septal defects.

BACKGROUND: Adult patients with a small, unrepaired atrial septal defect (ASD) have higher mortality and increased risk of several comorbidities compared to general population. Further, reduced submaximal and peak exercise capacity was recently demonstrated in these patients. The mechanisms behind these findings remain unexplained and, therefore, biventricular contractility during exercise was assessed by evaluating the force-frequency relationship in the same group of patients. METHODS: Adults patients with a small, unrepaired ASD and healthy age- and gender-matched controls were examined using echocardiography during supine bicycle exercise. Continuous tissue velocity Doppler was used to evaluate isovolumetric acceleration (IVA) and systolic velocities during an incremental workload protocol. All data were analyzed post hoc in a blinded fashion. RESULTS: We included 30 patients previously diagnosed with a small, unrepaired ASD (mean age 35 years, 63% female) and 25 controls (mean age 34 years, 64% female). Patients had similar values of IVA and systolic velocities at rest when compared with the healthy controls. Further, no differences in IVA was found at peak heart rate for neither the left ventricle (90 ± 39 vs 129 ± 68 cm/s2 , P = 0.1547) nor the right ventricle (128 ± 56 vs 154 ± 56 cm/s2 , 0.5691). There were no correlations between peak velocities and the lower exercise capacity previously reported in these patients. CONCLUSION: Adult patients with a small, unrepaired ASD have normal biventricular contractility at rest and during exercise when compared with healthy peers. Consequently, the pathophysiological mechanisms behind the impaired exercise capacity previously demonstrated in these patients remains unknown and will be a target for future work.

Lifelong burden of small unrepaired atrial septal defect: Results from the Danish National Patient Registry.

BACKGROUND: Adult patients with small, unrepaired atrial septal defects (ASD) have higher late mortality than the background population. In this nationwide study, we characterize the late natural history of adults with small, unrepaired ASD. METHODS: Using the Danish National Patient Registry, we included all Danish patients, diagnosed between 1953 and 2011 with an unrepaired ASD. Additionally, all patients, aged 18-65, were invited for clinical testing. Patients also completed a general health survey for comparison with the general population. RESULTS: We identified 723 patients with a small unrepaired ASD. Since the time of diagnosis, 182 patients had died, with an average lifespan of 63 years. The most common cause of death was heart failure. Furthermore, ASD patients had a higher burden of chronic disease than the general population (38.2% vs. 26.9%; p = 0.005), particularly lung disease (3.6% vs. 0.9%; p = 0.008). A total of 153 patients (mean age 32 y) underwent additional testing. On echocardiography an open defect was verified in 19.6% (n = 30) of the patients, of which half subsequently underwent intervention. Interestingly, 6-minute walking distance was markedly reduced (p < 0.0001 compared to normative values) no matter whether the defect was open or closed by echocardiography. Finally, 25.5% of the patients often felt stressed or nervous as compared with 16.3% of the general population (p = 0.004). CONCLUSIONS: Patients with small, unrepaired ASD in adult life have reduced lifespan, more chronic diseases, impaired submaximal exercise capacity, and higher levels of stress than the general population. The current guidelines for intervention and follow-up may need to be reconsidered.

Small unrepaired atrial septal defects display impaired exercise capacity compared with healthy peers.

OBJECTIVE: Adult patients with small, unrepaired atrial septal defects have an increased risk of pneumonia, atrial fibrillation, and stroke. Furthermore, they have higher late mortality than the background population. The functional capacity is unknown in these patients. Therefore, our objective was to determine exercise capacity in adult patients diagnosed with an unrepaired atrial septal defect compared to healthy controls. DESIGN: A cross-sectional study. PATIENTS: Adult patients with small, unrepaired atrial septal defects, aged 18-65, diagnosed between 1953 and 2011. INTERVENTIONS: Cardiopulmonary exercise test was performed using an incremental bicycle test and gas exchange was measured using breath-by-breath technique. OUTCOME MEASURES: Primary outcome was peak oxygen uptake, secondary outcome was maximal workload and ventilatory anaerobic threshold. RESULTS: We included 32 patients previously diagnosed with a small, unrepaired atrial septal defect and 16 healthy, age- and gender-matched controls (age 36.3 ± 13 years). Patients were divided into two groups based on whether the atrial septal defect was open (age 36.3 ± 11 years) or spontaneously closed (age 36.8 ± 14 years) since time of diagnosis. No differences in demographic characteristics or weekly exercise levels were found. Both patient groups reached lower peak oxygen uptake (open: 31.7 ± 11 mL/kg/min; spontaneously closed: 29.7 ± 6.9 mL/kg/min) compared with controls (42.6 ± 6.1 mL/kg/min; P = .0001). Workload (open: 2.6 ± 1.0 watt/kg; spontaneously closed: 2.5 ± 0.6 watt/kg) and aerobic capacity (open: 21.4 ± 8.7 mL/kg/min; spontaneously closed: 22.5 ± 6.5 mL/kg/min) was also poorer in patients compared to controls (workload: 3.5 ± 0.5 watt/kg; P = .0006, aerobic capacity: 31.3 ± 6.8 mL/kg/min; P = .0007). CONCLUSION: Adult patients with a diagnosis of small, unrepaired atrial septal defect have significantly impaired exercise capacity when compared to healthy controls. The impairment was present even if, by the time of assessment, the defect had closed spontaneously. The pathophysiological mechanisms behind the impaired exercise capacity demonstrated in these patients remain unexplained and will be a target for future work.

Long-term mortality in patients with atrial septal defect: a nationwide cohort-study.

Aims: In this nationwide cohort of atrial septal defect (ASD) patients, the largest to date, we report the longest follow-up time with and without closure in childhood and adulthood compared with a general population cohort. Methods and results: Using population-based registries, we included Danish individuals born before 1994 who received an ASD diagnosis between 1959 and 2013. All diagnoses were subsequently validated (n = 2277). Using the Kaplan-Meier estimates and Cox proportional hazards regression adjusted for sex, birth year, and a modified Charlson Comorbidity Index, we compared the mortality of ASD patients with that of a birth year and sex matched general population cohort. The median follow-up from ASD diagnosis was 18.1 years (range 1-53 years). Patients with ASD had a higher mortality [adjusted hazard ratio (HR): 1.7; 95% confidence interval (CI): 1.5-1.9] compared with the general population cohort. The adjusted HR 30 days after closure was 1.4 (95% CI: 1.2-1.7), and it was 2.4 (95% CI: 2.0-2.9) for patients without closure. Conclusion: Overall, ASD patients had a higher long-term mortality than a general population cohort matched on birth year and gender. Our data indicate a lower relative mortality of those ASD patients undergoing closure than the ASD patients not undergoing closure.