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Ischemic heart disease in children and young adults with congenital heart disease in Sweden
IJCA-25212; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx
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Ischemic heart disease in children and young adults with congenital heart disease in Sweden Maria Fedchenko ⁎,1, Zacharias Mandalenakis 1, Annika Rosengren 1, Georg Lappas 1, Peter Eriksson 1, Kristofer Skoglund 1, Mikael Dellborg 1 Adult Congenital Heart Unit, Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden Institute of Medicine, Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Sweden
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Article history: Received 12 April 2017 Received in revised form 28 June 2017 Accepted 29 June 2017 Available online xxxx Keywords: Congenital heart disease Ischemic heart disease Acute myocardial infarction
a b s t r a c t Background: An increasing proportion of congenital heart disease (CoHD) patients survive to an age associated with increased risk of developing ischemic heart disease (IHD). The aim was to investigate the risk of developing IHD among children and young adults with CoHD. Methods: Using the Swedish National Patient Register, we created a cohort of all CoHD patients born between January 1970 and December 1993. Ten controls matched for age, sex, county were randomly selected from the general population for each patient (n = 219,816). Patients and controls were followed from birth until first IHD event, death, or December 31, 2011. Results: We identified 21,982 patients with CoHD (51.6% men), mean follow-up was 26.4 (21.2–33.9) years. CoHD patients had 16.5 times higher risk of being hospitalized with or dying from IHD compared to controls (95% CI: 13.7–19.9), p b 0.0001. Patients with conotruncal defects and severe nonconotruncal defects, had the highest IHD incidence rate (71.1 and 56.3 cases per 100,000 person-years, respectively, compared to 2.9 and 2.3 in controls). Hypertension and diabetes were less common among CoHD patients with IHD than among controls with IHD (hypertension 9.7% vs 19.7%, diabetes 1.8% vs 7.7% in CoHD patients and controls). Patients with aortic coarctation did not have a specific increase in the risk of developing IHD or acute myocardial infarction. Conclusions: In this large case-control cohort study, the relative risk of developing IHD was markedly higher in CoHD patients than in controls. However, the absolute risk was low in both groups. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Congenital heart disease (CoHD) is one of the most common congenital malformations in newborns and occurs in about 1% of live births [1]. Currently, N90% of children with CoHD reach adulthood and the number of adults with CoHD is constantly growing as a result of the advances in both surgical and medical management in patients with CoHD over recent decades [2–6]. However, increasing survival and median age in patients with CoHD will result in an increased risk of developing acquired heart conditions such as ischemic heart disease (IHD), including acute myocardial infarction (AMI) [7,8].
Abbreviations: AMI, acute myocardial infarction; ASD, atrial septal defect; CI, confidence interval; CoA, coarctation of the aorta; CoHD, congenital heart disease; HR, hazard ratio; IHD, ischemic heart disease; VSD, ventricular septal defect. ⁎ Corresponding author at: Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska University Hospital/Östra, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden. E-mail address: [email protected] (M. Fedchenko). 1 Statement of authorship: This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
IHD in patients with CoHD may have several causes: conventional cardiovascular risk factors have been implicated as the major cause of coronary artery disease in adult patients with CoHD [4]; anomalous coronary anatomy may be an important contributor [5]; and surgical transposition of coronary arteries, with increased risk of postoperative stenosis, may potentially promote early atherosclerosis and premature coronary artery disease [9]. In addition, shunting with paradoxical embolism to the coronary arteries may be a possible cause of AMI in patients with CoHD [10]. The overall prevalence of coronary artery disease in adults with CoHD, as determined by coincidental and/or preoperative coronary angiography, varied between 1% in a large registry study [8] to 9.2% in a single-center study [11]. In the United States, coronary artery disease is now the most common cause of death in adult patients with noncyanotic heart defects [12]. Because of the major clinical implications of coronary artery disease such as IHD, the large discrepancies in the reported prevalence in adults with CoHD call for further studies on this matter. The aim of our study was, therefore, to investigate the risk of IHD in children and young adults with CoHD compared to matched controls.
http://dx.doi.org/10.1016/j.ijcard.2017.06.120 0167-5273/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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M. Fedchenko et al. / International Journal of Cardiology xxx (2017) xxx–xxx
2. Methods
2.4. Ethical approval
2.1. Study population
All national registration numbers were removed and replaced with a code in the final data set by the National Board of Health and Welfare in Sweden. The study complied with the Declaration of Helsinki and was approved by the Gothenburg Regional Research Ethics Board.
In the present study, we used linked data from the Swedish National Inpatient Register, the Swedish National Outpatient Register, and Cause of Death Register. The Swedish National Inpatient Register was initiated in 1964 with full national coverage from 1987 onwards. It is mandatory for all health care providers to report discharge diagnoses to the register. From 1970 onwards the register contains data from all hospitals performing cardiothoracic surgeries, and from 2001 it also contains data on all hospital outpatient visits, both in the public and the private sector. Currently, N99% of all discharge diagnoses are recorded in the Swedish National Inpatient Register [13]. From the Swedish National Inpatient Register, Swedish National Outpatient Register and the Cause of Death Register we identified 21,982 patients who were born between January 1970 and December 1993 and who had a diagnosis of CoHD as a principal or contributory diagnosis at any time until December 2011. 115 CoHD patients (0,52%) were identified from the Cause of Death Register only. We collected follow-up data on first IHD event for all patients until death, emigration, or the end of the study (December 31, 2011). We also included in the study the following comorbidities diagnosed prior or coinciding with the index IHD event: hypertension, diabetes mellitus, atrial fibrillation, and congestive heart failure. Each patient with a CoHD diagnosis was matched with 10 individuals from the general population without CoHD. Matching was by sex, age, and county of residence. For four of the CoHD patients, only nine controls were available for matching. All diagnoses were coded according to the International classification of Disease (ICD) 8th, 9th, and 10th editions. For ICD-8 and ICD-9 editions, the Swedish ICD version was used. The study population has been described previously [6].
2.2. Definitions The list of all CoHD diagnoses is described in Supplementary Table 1. All diagnoses were made by the discharging physician, using international standards and definitions such as the WHO-definition of acute myocardial infarction. IHD was defined as codes 410–414 in ICD-8 and ICD-9 and as codes I20–I25 in ICD-10. Myocardial infarction was defined as code 410 in ICD-8 and ICD-9 and as code I21 in ICD-10. Hypertension was defined as codes 401–405 (ICD-8 and ICD-9) or I10–I15 (ICD-10). Diabetes mellitus was defined as code 250 (ICD-8 and ICD-9) or codes E10–E14 (ICD-10). Atrial fibrillation was defined as code 427.92 (ICD-8) or 427D (ICD-9) or I48 (ICD-10). Congestive heart failure was defined as code 427.00 (ICD-8) or 428 (ICD-9) or I50 (ICD-10).
2.3. CoHD classification The CoHD diagnoses were classified according to a hierarchical classification system described by Liu et al. [14] and used in published studies [15–17]. Lesion group 1, “conotruncal defects”, was defined as common truncus, aortopulmonary septum defect, transposition of great vessels, and tetralogy of Fallot. Lesion group 2, “severe nonconotruncal defects”, was defined as endocardial cushion defects, common ventricle, and hypoplastic left heart syndrome. Lesion group 3, “CoA”, was defined as coarctation of the aorta and lesion group 4, “VSD”, included ventricular septal defect and other defects of the cardiac septum. Lesion group 5, “ASD”, was defined as atrial septal defect, and lesion group 6 included all other heart and circulatory system anomalies and all CoHD diagnoses not included in the five groups above. Supplementary Table 2 shows the ICD-8, ICD-9, and ICD-10 diagnoses for the CoHD classification.
2.5. Statistics Descriptive statistics were used to present the characteristics of the study population at birth. Percentages of patients and controls who were diagnosed with risk factors for IHD (hypertension and diabetes) before and up to the date of their IHD diagnosis were calculated, as well as percentages with other cardiac comorbidities (atrial fibrillation and congestive heart failure). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from a Cox regression model controlling for age and sex, in order to compare rates of developing IHD between cases and controls during the follow-up period. The time scale in our model was age. Those who had emigrated or were still alive at 31 December 2011 were censored, as were those who had a non-IHDrelated cause of death. Cumulative incidence functions of IHD are presented for different birth periods and for cases and controls separately. Death from non-IHD-related causes is the competing event. p-Values b 0.05 were considered statistically significant. We used SAS software (version 9.4; SAS Institute, Cary, NC, USA) and R software (version 3.1; R Foundation for Statistical Computing, Vienna, Austria) to perform all statistical analyses. 3. Results We identified a total of 21,982 patients with CoHD (51.6% men) and 219,816 controls born between January 1970 and December 1993. The characteristics of the CoHD population and controls are shown in Supplementary Table 3. The median and mean age at CoHD diagnosis as indicated by the Swedish Patient Register was 4.2 (interquartile range 17.1) and 9.6 (standard deviation ±11.3) years, respectively. 3.1. Risk of ischemic heart disease and acute myocardial infarction Table 1 shows that the risk in all CoHD patients of being diagnosed with IHD was 16.5 times higher than in controls (95% CI: 13.7– 19.9), p b 0.0001. A higher proportion of controls than CoHD patients were diagnosed with IHD in hospital outpatient clinics (controls: 23.5%, n = 43/183; CoHD patients: 18.0%, n = 50/278). 13 (4.7%) CoHD patients with IHD in our cohort were identified from the Cause of Death Register compared to 6 controls (3.3%). Approximately one third of CoHD patients who were diagnosed with IHD had AMI as their first IHD event (33.5%, n = 93/278), which was similar to controls (30.1%, n = 55/183). For controls with a diagnosis of IHD, the prevalence of angina pectoris as the first IHD event was higher than for CoHD patients (controls: 33.9%, n = 62/183; CoHD patients: 21.2%, n = 59/278). More CoHD patients with angina were diagnosed in hospital based outpatient clinics compared to controls with angina (CoHD patients: 27.1%, n = 16/59; controls: 22.6%, n = 14/62). Female, compared to male sex was associated with a lower risk of IHD in both groups (CoHD patients: HR 0.74, CI 0.59–0.94; controls: HR 0.79, CI 0.59–1.1). Overall, the incidence rates of IHD and AMI were much higher in the CoHD group than in the control group. Patients with the most complex congenital heart conditions, conotruncal defects and severe nonconotruncal defects (lesion groups 1 and 2), had the highest incidence rate of IHD, with 71.1 and 56.3 cases per 100,000 personyears, respectively. Patients with ventricular septal defect, who constituted almost one fifth of the CoHD population (19.9%), had the lowest incidence rate of IHD, with 31.2 IHD cases per 100,000 person-years.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
M. Fedchenko et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Table 1 Relative risk of ischemic heart disease in patients with congenital heart disease compared to matched controls, according to six CoHD lesion groups. Lesion group
Cases IHD (n)/total no. of patients in lesion group
Controls IHD (n)/total no. of controls in lesion group
IHD per 100,000 person-years, cases (n)
IHD per 100,000 person-years, controls (n)
HR for IHD (CI, 95%)
All CoHD 1. Conotruncal defectsa 2. Severe nonconotruncal defectsb 3. Coarctation of the aortac 4. Ventricular septal defectd 5. Atrial septal defecte 6. Other heart and circulatory system anomaliesf
278/21,982 33/2022 14/1087 16/1306 36/4369 26/2405 153/10,793
183/219,816 17/20,230 7/10,870 8/13,060 31/43,689 26/24,049 94/107,918
46.8 71.1 56.3 44.6 31.2 39.1 50.2
2.9 2.9 2.3 2.1 2.6 3.4 3.0
16.5 (13.7–19.9) 25.8 (14.4–46.4) 26.3 (10.6–65.3) 21.5 (9.2–50.3) 12.5 (7.7–20.2) 10.4 (6.0–17.9) 17.0 (13.2–22.0)
CI = confidence interval; CoHD = congenital heart disease; HR = hazard ratio; IHD = ischemic heart disease. a Defined as common truncus, aortopulmonary septum defect, transposition of great vessels, tetralogy of Fallot. b Defined as endocardial cushion defects, common ventricle, hypoplastic left heart syndrome. c Defined as coarctation of the aorta. d Defined as ventricular septal defect. e Defined as atrial septal defect. f Defined as diagnoses not classified into the other five lesion groups.
Patients with aortic coarctation had an intermediate incidence rate of 44.6 IHD cases per 100,000 person-years. Patients with the most complex congenital heart defects (lesion group 2) had the highest proportion of AMI as the first IHD event (64.3%) as shown in Table 2, but they constituted only a minority of all IHD cases. There were only two cases of AMI in patients with aortic coarctation, constituting 12.5% of IHD cases in this patient group. Patients with aortic coarctation also had the lowest increase in relative HR for AMI as compared to patients with other congenital lesions (Table 2). Fig. 1 shows that the incidence of IHD increases exponentially in CoHD patients above the age of 18 years. However, non-IHD-related mortality was significantly more common in CoHD patients than in controls also early in life. Supplementary Fig. 2 shows the cumulative incidence for IHD according to the six lesion groups. Patients with other heart and circulatory system anomalies (lesion group 6) had the highest cumulative incidence of IHD, while patients with aortic coarctation (lesion group 3) had the lowest cumulative incidence of IHD. Of all CoHD patients, 38.0% (n = 8352) underwent at least one surgical procedure. A higher percentage of CoHD patients with IHD had undergone surgical procedures compared to CoHD patients without IHD (63.0%, n = 175/278 compared to 37.1%, n = 103/278). Of the 93 CoHD patients with AMI, 68.8% (n = 64) had had a surgical procedure. 3.2. Cardiovascular risk factors and comorbidities There were several differences in rates of cardiovascular risk factors and comorbidities in the CoHD patients with IHD and the controls with IHD, as shown in Table 3. Hypertension and diabetes were more
common among controls with IHD than among CoHD patients with IHD. There were no significant differences in the incidence of atrial fibrillation prior to IHD diagnosis between the CoHD patients and controls. Congestive heart failure was significantly more common in CoHD patients than in controls (CoHD patients: 19.4%, n = 54; controls: 7.1%, n = 13). 3.3. Incidence of ischemic heart disease according to birth cohorts For all CoHD birth cohorts, the incidence rate of IHD rapidly increased from around 20 years of age, see Supplementary Fig. 3; a corresponding rapid increase in the cumulative incidence of IHD was not observed for the controls. 4. Discussion In this large registry study we found that the risk of IHD in children and young adults with CoHD in Sweden was 16.5 times higher (CI: 13.7–19.9) than in matched controls. However, the absolute risk of IHD in patients with CoHD was low, with only 278 events in 21,982 CoHD patients, or 0.45 cases per thousand person-years. Of note, CoHD patients with a diagnosis of IHD had a significantly lower incidence of conventional cardiovascular risk factors (hypertension and diabetes) compared to controls diagnosed with IHD. Prior to and at time of IHD diagnosis, diabetes was found in 1.8% and hypertension in 9.7% of CoHD patients, compared to 7.7% and 19.7%, respectively, in controls; this illustrates the potential for non-conventional risk factors to be of importance in the development of IHD in CoHD patients. Our findings suggest that atherosclerosis may not be the dominant
Table 2 Incidence of acute myocardial infarction, ischemic heart disease and percentage of acute myocardial infarction as first ischemic heart disease event, for all CoHD lesion groups. Lesion group
AMI cases (n)/ total no. patients
AMI as % of all IHD, cases
AMI Controls (n)/ total no. patients
AMI as % of all IHD, controls
HR AMI compared to controls (95% CI)
All groups 1. Conotruncal defectsa 2. Severe nonconotruncal defectsb 3. Coarctation of the aortac 4. Ventricular septal defectd 5. Atrial septal defecte 6. Other heart and circulatory system anomaliesf
93/278 12/2022 9/1087 2/1306 13/4369 12/2405 45/10,793
33.5% 36.4% 64.3% 12.5% 36.1% 46.2% 29.6%
30.1% 2/20,230 1/10,870 2/13,060 9/43,689 5/24,049 36/107,918
55/183 11.8% 14.3% 25.0% 29.0% 19.2% 38.3%
18.4 (13.2–25.7) 80.9 (18.1–361.9) 114.7 (14.5–905.8) 10.7 (1.5–76.2) 15.5 (6.6–36.2) 24.9 (8.8–70.6) 13.1 (8.5–20.3)
AMI = acute myocardial infarction; CI = confidence interval; CoHD = congenital heart defect; HR = hazard ratio; IHD = ischemic heart disease. a Defined as common truncus, aortopulmonary septum defect, transposition of great vessels, tetralogy of Fallot. b Defined as endocardial cushion defects, common ventricle, hypoplastic left heart syndrome. c Defined as coarctation of the aorta. d Defined as ventricular septal defect. e Defined as atrial septal defect. f Defined as diagnoses not classified into the other five lesion groups.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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M. Fedchenko et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Fig. 1. Cumulative incidence of ischemic heart disease in the study population, with death in non-IHD related causes as the competing risk. CoHD = congenital heart disease; IHD = ischemic heart disease.
pathogenetic factor in the development of IHD in our relatively young cohort of CoHD patients. There is today no universally accepted classification system for CoHD diagnoses. We used a previously described hierarchical classification system for CoHD and found that the patients with the most severe congenital heart conditions, namely, conotruncal defects and severe nonconotruncal defects, had the highest probability of being diagnosed with IHD. In a recent large registry study based on the same registry data as in the current study, our group found that patients with the most severe CoHD conditions also had the highest incidence of ischemic strokes [18]. In the present study, patients with severe nonconotruncal defects also had the highest proportion of AMI as their first IHD event. A possible explanation for that could be that AMI and IHD in these patients is related to previous surgical procedures. Previous studies have reported that patients with transposition of the great arteries who undergo arterial switch procedures and transfer of the coronary arteries have a higher risk of coronary events [19,20]. Further, severe forms of CoHD have been associated with a relatively high prevalence of congenital anomalies of the coronary arteries [21,22]. The incidence of IHD in our study is in line with the results reported in a large registry study from Canada [8]. Yalonetsky et al. found that coronary artery disease was present in around 1% (n = 141) in a large population of 12,124 CoHD patients. In a retrospective study on 250 CoHD patients referred for coronary angiography, Giannakoulas et al. found a 9.2% prevalence of coronary artery disease. The mean age of the population was 51 ± 15 years. Comparisons with our study are problematic because of the heterogeneity of the populations studied. Aortic coarctation has historically been associated with a higher risk of coronary artery disease even after successful surgical repair [23,24]. Roifman et al. described a 4.9% prevalence of coronary artery disease in aortic coarctation patients and 3.5% in patients with ventricular septal defect [24]. In our study, 1.2% of aortic coarctation patients and 0.9% of ventricular septal defect patients were diagnosed with IHD during Table 3 Comorbidities in congenital heart disease patients and controls with ischemic heart disease diagnosed prior to, or coinciding, with index ischemic heart disease event.
Hypertension Diabetes mellitus Atrial fibrillation Heart failure CoHD = congenital heart disease.
CoHD % (n)
Controls % (n)
9.7 (27) 1.8 (5) 6.5 (18) 19.4 (54)
19.7 (36) 7.7 (14) 6.0 (11) 7.1 (13)
follow-up. However, the patients described by Roifman were slightly older and had a higher prevalence of conventional risk factors: hypertension was present in 45% of the aortic coarctation group and 16% of the ventricular septal defect group, and they had a much higher prevalence of diabetes (6%) compared to our finding of only 1.8%. However, neither study found any major or significant increase in the risk of IHD or AMI among patients with aortic coarctation as compared to patients with other CoHD diagnoses. In addition, we found that patients with aortic coarctation had the lowest relative increase in HR of AMI as compared to the other groups. Our data would thus add further to the notion that patients with aortic coarctation do not have a specific increase in the risk of developing coronary artery disease. We found the cumulative incidence of IHD to be higher in the birth cohort 1980–1989 than the birth cohort 1970–1979 for patients of the same age. A possible explanation for this is that patients in the earlier birth cohort may have had a higher early mortality rate and therefore a lower risk of developing and being diagnosed with IHD. This is illustrated in Fig. 1, which shows the cumulative incidence of IHD and a competing risk event (non-IHD-related death). Our group has previously reported data showing that the mortality risk has declined between 1970 and 1989 [6] but the present analysis suggests that the increased risk of IHD has not declined in a similar manner. Our study is the first large registry study to investigate the risk of IHD in children and young adults with CoHD and the first to compare this risk with a matched control population without CoHD. The strength of this study is its large scale: it includes almost all CoHD patients in Sweden born between 1970 and 1993, with minimal loss to follow-up. Our findings are clinically important because adults with CoHD now live longer and the CoHD population is growing and ageing. Fig. 1 shows that the cumulative incidence of IHD is consistently higher in CoHD patients compared to controls from an early age and increases more rapidly in CoHD patients from about age 18. We cannot deduce the exact mechanisms for IHD in our population as the use of anonymized data meant that individual medical records could not be accessed. We believe that the mechanisms for IHD in young CoHD patients are multifactorial. Previous surgical procedures and associated physiological responses might contribute to the development of ischemia. Many patients living with CoHD have reduced maximal oxygen uptake in combination with increased oxygen demand due to volume pressure overload; they are thereby exposed to myocardial ischemia, even in the presence of normal coronaries [25]. Further, many CoHD patients undergo several radiological investigations from a young age and are hence more exposed to radiation of the thorax, which might accelerate
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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atherosclerosis [26]. Also, a sedentary lifestyle and the presence of conventional risk factors such as diabetes [27] and hypertension [28] in CoHD patients might contribute to the development of atherosclerosis and IHD. Our study on a relatively young cohort of CoHD patients shows that the risk of IHD is generally increased in CoHD patients independently of the complexity of the lesions. This might suggest considerations of more intense monitoring and lowered thresholds for treatment of conventional risk factors as well as timely and proper identification of disease-specific risk factors in CoHD patients. 5. Limitations As in all registry studies, there is a risk of misclassification of both CoHD and IHD diagnoses in our study. Some diagnoses of IHD might have been classified differently in the ICD-8, ICD-9, and ICD-10 versions. Further, diagnosis of IHD might be challenging in patients with CoHD due to the prevalence of ECG changes secondary to previous surgical procedures and due to a possible increase in highly sensitive biomarkers even in the absence of necrosis (e.g. because of heart failure or atrial fibrillation). Nonetheless, the diagnoses in the patient registers we used have been shown to have a high level of validity, from 85 to 95% [13], and even higher in the diagnosis of MI and angina pectoris [13, 29]. The validity of these diagnoses in CoHD patients has not been specifically studied. Both underdiagnosis and overdiagnosis might occur more in CoHD patients than in controls in the presence of the same symptoms. There is no universal definition of angina; even so, the proportion of AMI as a percentage of all IHD in this young population was similar for cases and controls, or about one in three, and accordingly it is unlikely that the differences that we found would have been due to non-specific chest pain being present to a larger extent in the CoHD group. One of the main limitations in our study is that outpatient diagnoses have only been registered since 2001, which could have led to underestimation of the true IHD incidence. We cannot rule out that there could be a number of patients with IHD who were diagnosed and followed only in the outpatient clinics. Although the loss to follow-up in registry studies is generally low, a small proportion of the patients in our study were lost to follow-up, for example by moving abroad. Since the patients were followed from birth, there were no comorbidities at baseline, and we could not perform a standard logistic regression analysis to control for risk factors. Also, there might have been an underestimation of comorbidities, both in the CoHD group and in controls, if the diagnosis of cardiovascular risk factors was established only in primary care. There could also be a potential detection bias in CoHD as these patients are more closely monitored in the health care setting as compared to healthy controls. However, we do not believe that this leads to increased IHD risk estimates as we study young patients with or without CoHD. Among such young patients, b 42 years old by design of our study, there are probably other, more plausible explanations, for the increased risk of IHD than atherosclerosis. Finally, we were unable to access individual medical records and have no information on smoking and family history of coronary artery disease. Also, the more intricate mechanisms behind each IHD or AMI diagnosis cannot be determined, nor whether the IHD was due to arteriosclerosis, embolism or a consequence of previous surgical procedures. 6. Conclusions This large registry study on children and young adults with CoHD in Sweden shows that CoHD patients have a 16.5 times greater risk of being diagnosed with IHD compared to controls. However, the absolute risk of IHD is low in both groups. Patients with severe nonconotruncal defects and patients with conotruncal defects had the highest relative risk, while patients with atrial septal defect and ventricular septal defect had the lowest risk. Patients with aortic coarctation do not have a
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specific increase in the risk of developing IHD or AMI. More studies on IHD in CoHD patients are needed to explore the exact mechanisms of IHD in this heterogeneous patient group. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.06.120. Funding The present study was supported by grants from the Swedish state (under the agreement between the Swedish government and the county councils concerning economic support of research and education of doctors, ALF-agreement, grants ALFGBG-427301 and ALFGBG-435211); grants from the Swedish Heart and Lung Foundation (2015-0438 and 2009-0724) and the Swedish Research Council (340-2013-5187 and 521-2013-4236). The funding sources of the present study had no role in the study design, data collection or analysis, data interpretation, or in writing of the report. Conflicts of interest None. References [1] B. Khoshnood, N. Lelong, L. Houyel, A.C. Thieulin, J.M. Jouannic, S. Magnier, et al., Prevalence, timing of diagnosis and mortality of newborns with congenital heart defects: a population-based study, Heart 98 (22) (2012) 1667–1673. [2] A.J. Marelli, A.S. Mackie, R. Ionescu-Ittu, E. Rahme, L. Pilote, Congenital heart disease in the general population: changing prevalence and age distribution, Circulation 115 (2) (2007) 163–172. [3] A.J. Marelli, J. Therrien, A.S. Mackie, R. Ionescu-Ittu, L. Pilote, Planning the specialized care of adult congenital heart disease patients: from numbers to guidelines; an epidemiologic approach, Am. Heart J. 157 (1) (2009) 1–8. [4] P. Moons, L. Bovijn, W. Budts, A. Belmans, M. Gewillig, Temporal trends in survival to adulthood among patients born with congenital heart disease from 1970 to 1992 in Belgium, Circulation 122 (22) (2010) 2264–2272. [5] M. Olsen, T.D. Christensen, L. Pedersen, S.P. Johnsen, V.E. Hjortdal, Late mortality among Danish patients with congenital heart defect, Am. J. Cardiol. 106 (9) (2010) 1322–1326. [6] Z. Mandalenakis, A. Rosengren, K. Skoglund, G. Lappas, P. Eriksson, M. Dellborg, Survivorship in children and young adults with congenital heart disease in Sweden, JAMA Intern Med. 177 (2) (2017) 224–230. [7] O. Tutarel, A. Kempny, R. Alonso-Gonzalez, R. Jabbour, W. Li, A. Uebing, et al., Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality, Eur. Heart J. 35 (11) (2014) 725–732. [8] S. Yalonetsky, E.M. Horlick, M.D. Osten, L.N. Benson, E.N. Oechslin, C.K. Silversides, Clinical characteristics of coronary artery disease in adults with congenital heart defects, Int. J. Cardiol. 164 (2) (2013) 217–220. [9] H. Sugiyama, E. Tsuda, H. Ohuchi, O. Yamada, I. Shiraishi, Chronological changes in stenosis of translocated coronary arteries on angiography after the arterial switch operation in children with transposition of the great arteries: comparison of myocardial scintigraphy and angiographic findings, Cardiol. Young (2015) 1–6. [10] W.C. Wasek, W. Samul, R. Ryczek, A. Skrobowski, Unique case of ST-segmentelevation myocardial infarction related to paradoxical embolization and simultaneous pulmonary embolization: clinical considerations on indications for patent foramen ovale closure in no-guidelines land, Circulation 131 (13) (2015) 1214–1223. [11] G. Giannakoulas, K. Dimopoulos, R. Engel, O. Goktekin, Z. Kucukdurmaz, M.A. Vatankulu, et al., Burden of coronary artery disease in adults with congenital heart disease and its relation to congenital and traditional heart risk factors, Am. J. Cardiol. 103 (10) (2009) 1445–1450. [12] P. Pillutla, K.D. Shetty, E. Foster, Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005, Am. Heart J. 158 (5) (2009) 874–879. [13] J.F. Ludvigsson, E. Andersson, A. Ekbom, M. Feychting, J.L. Kim, C. Reuterwall, et al., External review and validation of the Swedish national inpatient register, BMC Public Health 11 (2011) 450. [14] S. Liu, K.S. Joseph, W. Luo, J.A. Leon, S. Lisonkova, M. Van den Hof, et al., Effect of folic acid food fortification in Canada on congenital heart disease subtypes, Circulation 134 (9) (2016) 647–655. [15] L.D. Botto, A.E. Lin, T. Riehle-Colarusso, S. Malik, A. Correa, National Birth Defects Prevention S, Seeking causes: classifying and evaluating congenital heart defects in etiologic studies, Birth Defects Res. A Clin. Mol. Teratol. 79 (10) (2007) 714–727. [16] N. Oyen, G. Poulsen, H.A. Boyd, J. Wohlfahrt, P.K. Jensen, M. Melbye, National time trends in congenital heart defects, Denmark, 1977–2005, Am. Heart J. 157 (3) (2009) 467–473 (e1). [17] S. Liu, K.S. Joseph, S. Lisonkova, J. Rouleau, M. Van den Hof, R. Sauve, et al., Association between maternal chronic conditions and congenital heart defects: a population-based cohort study, Circulation 128 (6) (2013) 583–589.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Ischemic heart disease in children and young adults with congenital heart disease in Sweden Maria Fedchenko ⁎,1, Zacharias Mandalenakis 1, Annika Rosengren 1, Georg Lappas 1, Peter Eriksson 1, Kristofer Skoglund 1, Mikael Dellborg 1 Adult Congenital Heart Unit, Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden Institute of Medicine, Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Sweden
a r t i c l e
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Article history: Received 12 April 2017 Received in revised form 28 June 2017 Accepted 29 June 2017 Available online xxxx Keywords: Congenital heart disease Ischemic heart disease Acute myocardial infarction
a b s t r a c t Background: An increasing proportion of congenital heart disease (CoHD) patients survive to an age associated with increased risk of developing ischemic heart disease (IHD). The aim was to investigate the risk of developing IHD among children and young adults with CoHD. Methods: Using the Swedish National Patient Register, we created a cohort of all CoHD patients born between January 1970 and December 1993. Ten controls matched for age, sex, county were randomly selected from the general population for each patient (n = 219,816). Patients and controls were followed from birth until first IHD event, death, or December 31, 2011. Results: We identified 21,982 patients with CoHD (51.6% men), mean follow-up was 26.4 (21.2–33.9) years. CoHD patients had 16.5 times higher risk of being hospitalized with or dying from IHD compared to controls (95% CI: 13.7–19.9), p b 0.0001. Patients with conotruncal defects and severe nonconotruncal defects, had the highest IHD incidence rate (71.1 and 56.3 cases per 100,000 person-years, respectively, compared to 2.9 and 2.3 in controls). Hypertension and diabetes were less common among CoHD patients with IHD than among controls with IHD (hypertension 9.7% vs 19.7%, diabetes 1.8% vs 7.7% in CoHD patients and controls). Patients with aortic coarctation did not have a specific increase in the risk of developing IHD or acute myocardial infarction. Conclusions: In this large case-control cohort study, the relative risk of developing IHD was markedly higher in CoHD patients than in controls. However, the absolute risk was low in both groups. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Congenital heart disease (CoHD) is one of the most common congenital malformations in newborns and occurs in about 1% of live births [1]. Currently, N90% of children with CoHD reach adulthood and the number of adults with CoHD is constantly growing as a result of the advances in both surgical and medical management in patients with CoHD over recent decades [2–6]. However, increasing survival and median age in patients with CoHD will result in an increased risk of developing acquired heart conditions such as ischemic heart disease (IHD), including acute myocardial infarction (AMI) [7,8].
Abbreviations: AMI, acute myocardial infarction; ASD, atrial septal defect; CI, confidence interval; CoA, coarctation of the aorta; CoHD, congenital heart disease; HR, hazard ratio; IHD, ischemic heart disease; VSD, ventricular septal defect. ⁎ Corresponding author at: Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska University Hospital/Östra, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden. E-mail address: [email protected] (M. Fedchenko). 1 Statement of authorship: This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
IHD in patients with CoHD may have several causes: conventional cardiovascular risk factors have been implicated as the major cause of coronary artery disease in adult patients with CoHD [4]; anomalous coronary anatomy may be an important contributor [5]; and surgical transposition of coronary arteries, with increased risk of postoperative stenosis, may potentially promote early atherosclerosis and premature coronary artery disease [9]. In addition, shunting with paradoxical embolism to the coronary arteries may be a possible cause of AMI in patients with CoHD [10]. The overall prevalence of coronary artery disease in adults with CoHD, as determined by coincidental and/or preoperative coronary angiography, varied between 1% in a large registry study [8] to 9.2% in a single-center study [11]. In the United States, coronary artery disease is now the most common cause of death in adult patients with noncyanotic heart defects [12]. Because of the major clinical implications of coronary artery disease such as IHD, the large discrepancies in the reported prevalence in adults with CoHD call for further studies on this matter. The aim of our study was, therefore, to investigate the risk of IHD in children and young adults with CoHD compared to matched controls.
http://dx.doi.org/10.1016/j.ijcard.2017.06.120 0167-5273/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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2. Methods
2.4. Ethical approval
2.1. Study population
All national registration numbers were removed and replaced with a code in the final data set by the National Board of Health and Welfare in Sweden. The study complied with the Declaration of Helsinki and was approved by the Gothenburg Regional Research Ethics Board.
In the present study, we used linked data from the Swedish National Inpatient Register, the Swedish National Outpatient Register, and Cause of Death Register. The Swedish National Inpatient Register was initiated in 1964 with full national coverage from 1987 onwards. It is mandatory for all health care providers to report discharge diagnoses to the register. From 1970 onwards the register contains data from all hospitals performing cardiothoracic surgeries, and from 2001 it also contains data on all hospital outpatient visits, both in the public and the private sector. Currently, N99% of all discharge diagnoses are recorded in the Swedish National Inpatient Register [13]. From the Swedish National Inpatient Register, Swedish National Outpatient Register and the Cause of Death Register we identified 21,982 patients who were born between January 1970 and December 1993 and who had a diagnosis of CoHD as a principal or contributory diagnosis at any time until December 2011. 115 CoHD patients (0,52%) were identified from the Cause of Death Register only. We collected follow-up data on first IHD event for all patients until death, emigration, or the end of the study (December 31, 2011). We also included in the study the following comorbidities diagnosed prior or coinciding with the index IHD event: hypertension, diabetes mellitus, atrial fibrillation, and congestive heart failure. Each patient with a CoHD diagnosis was matched with 10 individuals from the general population without CoHD. Matching was by sex, age, and county of residence. For four of the CoHD patients, only nine controls were available for matching. All diagnoses were coded according to the International classification of Disease (ICD) 8th, 9th, and 10th editions. For ICD-8 and ICD-9 editions, the Swedish ICD version was used. The study population has been described previously [6].
2.2. Definitions The list of all CoHD diagnoses is described in Supplementary Table 1. All diagnoses were made by the discharging physician, using international standards and definitions such as the WHO-definition of acute myocardial infarction. IHD was defined as codes 410–414 in ICD-8 and ICD-9 and as codes I20–I25 in ICD-10. Myocardial infarction was defined as code 410 in ICD-8 and ICD-9 and as code I21 in ICD-10. Hypertension was defined as codes 401–405 (ICD-8 and ICD-9) or I10–I15 (ICD-10). Diabetes mellitus was defined as code 250 (ICD-8 and ICD-9) or codes E10–E14 (ICD-10). Atrial fibrillation was defined as code 427.92 (ICD-8) or 427D (ICD-9) or I48 (ICD-10). Congestive heart failure was defined as code 427.00 (ICD-8) or 428 (ICD-9) or I50 (ICD-10).
2.3. CoHD classification The CoHD diagnoses were classified according to a hierarchical classification system described by Liu et al. [14] and used in published studies [15–17]. Lesion group 1, “conotruncal defects”, was defined as common truncus, aortopulmonary septum defect, transposition of great vessels, and tetralogy of Fallot. Lesion group 2, “severe nonconotruncal defects”, was defined as endocardial cushion defects, common ventricle, and hypoplastic left heart syndrome. Lesion group 3, “CoA”, was defined as coarctation of the aorta and lesion group 4, “VSD”, included ventricular septal defect and other defects of the cardiac septum. Lesion group 5, “ASD”, was defined as atrial septal defect, and lesion group 6 included all other heart and circulatory system anomalies and all CoHD diagnoses not included in the five groups above. Supplementary Table 2 shows the ICD-8, ICD-9, and ICD-10 diagnoses for the CoHD classification.
2.5. Statistics Descriptive statistics were used to present the characteristics of the study population at birth. Percentages of patients and controls who were diagnosed with risk factors for IHD (hypertension and diabetes) before and up to the date of their IHD diagnosis were calculated, as well as percentages with other cardiac comorbidities (atrial fibrillation and congestive heart failure). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from a Cox regression model controlling for age and sex, in order to compare rates of developing IHD between cases and controls during the follow-up period. The time scale in our model was age. Those who had emigrated or were still alive at 31 December 2011 were censored, as were those who had a non-IHDrelated cause of death. Cumulative incidence functions of IHD are presented for different birth periods and for cases and controls separately. Death from non-IHD-related causes is the competing event. p-Values b 0.05 were considered statistically significant. We used SAS software (version 9.4; SAS Institute, Cary, NC, USA) and R software (version 3.1; R Foundation for Statistical Computing, Vienna, Austria) to perform all statistical analyses. 3. Results We identified a total of 21,982 patients with CoHD (51.6% men) and 219,816 controls born between January 1970 and December 1993. The characteristics of the CoHD population and controls are shown in Supplementary Table 3. The median and mean age at CoHD diagnosis as indicated by the Swedish Patient Register was 4.2 (interquartile range 17.1) and 9.6 (standard deviation ±11.3) years, respectively. 3.1. Risk of ischemic heart disease and acute myocardial infarction Table 1 shows that the risk in all CoHD patients of being diagnosed with IHD was 16.5 times higher than in controls (95% CI: 13.7– 19.9), p b 0.0001. A higher proportion of controls than CoHD patients were diagnosed with IHD in hospital outpatient clinics (controls: 23.5%, n = 43/183; CoHD patients: 18.0%, n = 50/278). 13 (4.7%) CoHD patients with IHD in our cohort were identified from the Cause of Death Register compared to 6 controls (3.3%). Approximately one third of CoHD patients who were diagnosed with IHD had AMI as their first IHD event (33.5%, n = 93/278), which was similar to controls (30.1%, n = 55/183). For controls with a diagnosis of IHD, the prevalence of angina pectoris as the first IHD event was higher than for CoHD patients (controls: 33.9%, n = 62/183; CoHD patients: 21.2%, n = 59/278). More CoHD patients with angina were diagnosed in hospital based outpatient clinics compared to controls with angina (CoHD patients: 27.1%, n = 16/59; controls: 22.6%, n = 14/62). Female, compared to male sex was associated with a lower risk of IHD in both groups (CoHD patients: HR 0.74, CI 0.59–0.94; controls: HR 0.79, CI 0.59–1.1). Overall, the incidence rates of IHD and AMI were much higher in the CoHD group than in the control group. Patients with the most complex congenital heart conditions, conotruncal defects and severe nonconotruncal defects (lesion groups 1 and 2), had the highest incidence rate of IHD, with 71.1 and 56.3 cases per 100,000 personyears, respectively. Patients with ventricular septal defect, who constituted almost one fifth of the CoHD population (19.9%), had the lowest incidence rate of IHD, with 31.2 IHD cases per 100,000 person-years.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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Table 1 Relative risk of ischemic heart disease in patients with congenital heart disease compared to matched controls, according to six CoHD lesion groups. Lesion group
Cases IHD (n)/total no. of patients in lesion group
Controls IHD (n)/total no. of controls in lesion group
IHD per 100,000 person-years, cases (n)
IHD per 100,000 person-years, controls (n)
HR for IHD (CI, 95%)
All CoHD 1. Conotruncal defectsa 2. Severe nonconotruncal defectsb 3. Coarctation of the aortac 4. Ventricular septal defectd 5. Atrial septal defecte 6. Other heart and circulatory system anomaliesf
278/21,982 33/2022 14/1087 16/1306 36/4369 26/2405 153/10,793
183/219,816 17/20,230 7/10,870 8/13,060 31/43,689 26/24,049 94/107,918
46.8 71.1 56.3 44.6 31.2 39.1 50.2
2.9 2.9 2.3 2.1 2.6 3.4 3.0
16.5 (13.7–19.9) 25.8 (14.4–46.4) 26.3 (10.6–65.3) 21.5 (9.2–50.3) 12.5 (7.7–20.2) 10.4 (6.0–17.9) 17.0 (13.2–22.0)
CI = confidence interval; CoHD = congenital heart disease; HR = hazard ratio; IHD = ischemic heart disease. a Defined as common truncus, aortopulmonary septum defect, transposition of great vessels, tetralogy of Fallot. b Defined as endocardial cushion defects, common ventricle, hypoplastic left heart syndrome. c Defined as coarctation of the aorta. d Defined as ventricular septal defect. e Defined as atrial septal defect. f Defined as diagnoses not classified into the other five lesion groups.
Patients with aortic coarctation had an intermediate incidence rate of 44.6 IHD cases per 100,000 person-years. Patients with the most complex congenital heart defects (lesion group 2) had the highest proportion of AMI as the first IHD event (64.3%) as shown in Table 2, but they constituted only a minority of all IHD cases. There were only two cases of AMI in patients with aortic coarctation, constituting 12.5% of IHD cases in this patient group. Patients with aortic coarctation also had the lowest increase in relative HR for AMI as compared to patients with other congenital lesions (Table 2). Fig. 1 shows that the incidence of IHD increases exponentially in CoHD patients above the age of 18 years. However, non-IHD-related mortality was significantly more common in CoHD patients than in controls also early in life. Supplementary Fig. 2 shows the cumulative incidence for IHD according to the six lesion groups. Patients with other heart and circulatory system anomalies (lesion group 6) had the highest cumulative incidence of IHD, while patients with aortic coarctation (lesion group 3) had the lowest cumulative incidence of IHD. Of all CoHD patients, 38.0% (n = 8352) underwent at least one surgical procedure. A higher percentage of CoHD patients with IHD had undergone surgical procedures compared to CoHD patients without IHD (63.0%, n = 175/278 compared to 37.1%, n = 103/278). Of the 93 CoHD patients with AMI, 68.8% (n = 64) had had a surgical procedure. 3.2. Cardiovascular risk factors and comorbidities There were several differences in rates of cardiovascular risk factors and comorbidities in the CoHD patients with IHD and the controls with IHD, as shown in Table 3. Hypertension and diabetes were more
common among controls with IHD than among CoHD patients with IHD. There were no significant differences in the incidence of atrial fibrillation prior to IHD diagnosis between the CoHD patients and controls. Congestive heart failure was significantly more common in CoHD patients than in controls (CoHD patients: 19.4%, n = 54; controls: 7.1%, n = 13). 3.3. Incidence of ischemic heart disease according to birth cohorts For all CoHD birth cohorts, the incidence rate of IHD rapidly increased from around 20 years of age, see Supplementary Fig. 3; a corresponding rapid increase in the cumulative incidence of IHD was not observed for the controls. 4. Discussion In this large registry study we found that the risk of IHD in children and young adults with CoHD in Sweden was 16.5 times higher (CI: 13.7–19.9) than in matched controls. However, the absolute risk of IHD in patients with CoHD was low, with only 278 events in 21,982 CoHD patients, or 0.45 cases per thousand person-years. Of note, CoHD patients with a diagnosis of IHD had a significantly lower incidence of conventional cardiovascular risk factors (hypertension and diabetes) compared to controls diagnosed with IHD. Prior to and at time of IHD diagnosis, diabetes was found in 1.8% and hypertension in 9.7% of CoHD patients, compared to 7.7% and 19.7%, respectively, in controls; this illustrates the potential for non-conventional risk factors to be of importance in the development of IHD in CoHD patients. Our findings suggest that atherosclerosis may not be the dominant
Table 2 Incidence of acute myocardial infarction, ischemic heart disease and percentage of acute myocardial infarction as first ischemic heart disease event, for all CoHD lesion groups. Lesion group
AMI cases (n)/ total no. patients
AMI as % of all IHD, cases
AMI Controls (n)/ total no. patients
AMI as % of all IHD, controls
HR AMI compared to controls (95% CI)
All groups 1. Conotruncal defectsa 2. Severe nonconotruncal defectsb 3. Coarctation of the aortac 4. Ventricular septal defectd 5. Atrial septal defecte 6. Other heart and circulatory system anomaliesf
93/278 12/2022 9/1087 2/1306 13/4369 12/2405 45/10,793
33.5% 36.4% 64.3% 12.5% 36.1% 46.2% 29.6%
30.1% 2/20,230 1/10,870 2/13,060 9/43,689 5/24,049 36/107,918
55/183 11.8% 14.3% 25.0% 29.0% 19.2% 38.3%
18.4 (13.2–25.7) 80.9 (18.1–361.9) 114.7 (14.5–905.8) 10.7 (1.5–76.2) 15.5 (6.6–36.2) 24.9 (8.8–70.6) 13.1 (8.5–20.3)
AMI = acute myocardial infarction; CI = confidence interval; CoHD = congenital heart defect; HR = hazard ratio; IHD = ischemic heart disease. a Defined as common truncus, aortopulmonary septum defect, transposition of great vessels, tetralogy of Fallot. b Defined as endocardial cushion defects, common ventricle, hypoplastic left heart syndrome. c Defined as coarctation of the aorta. d Defined as ventricular septal defect. e Defined as atrial septal defect. f Defined as diagnoses not classified into the other five lesion groups.
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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Fig. 1. Cumulative incidence of ischemic heart disease in the study population, with death in non-IHD related causes as the competing risk. CoHD = congenital heart disease; IHD = ischemic heart disease.
pathogenetic factor in the development of IHD in our relatively young cohort of CoHD patients. There is today no universally accepted classification system for CoHD diagnoses. We used a previously described hierarchical classification system for CoHD and found that the patients with the most severe congenital heart conditions, namely, conotruncal defects and severe nonconotruncal defects, had the highest probability of being diagnosed with IHD. In a recent large registry study based on the same registry data as in the current study, our group found that patients with the most severe CoHD conditions also had the highest incidence of ischemic strokes [18]. In the present study, patients with severe nonconotruncal defects also had the highest proportion of AMI as their first IHD event. A possible explanation for that could be that AMI and IHD in these patients is related to previous surgical procedures. Previous studies have reported that patients with transposition of the great arteries who undergo arterial switch procedures and transfer of the coronary arteries have a higher risk of coronary events [19,20]. Further, severe forms of CoHD have been associated with a relatively high prevalence of congenital anomalies of the coronary arteries [21,22]. The incidence of IHD in our study is in line with the results reported in a large registry study from Canada [8]. Yalonetsky et al. found that coronary artery disease was present in around 1% (n = 141) in a large population of 12,124 CoHD patients. In a retrospective study on 250 CoHD patients referred for coronary angiography, Giannakoulas et al. found a 9.2% prevalence of coronary artery disease. The mean age of the population was 51 ± 15 years. Comparisons with our study are problematic because of the heterogeneity of the populations studied. Aortic coarctation has historically been associated with a higher risk of coronary artery disease even after successful surgical repair [23,24]. Roifman et al. described a 4.9% prevalence of coronary artery disease in aortic coarctation patients and 3.5% in patients with ventricular septal defect [24]. In our study, 1.2% of aortic coarctation patients and 0.9% of ventricular septal defect patients were diagnosed with IHD during Table 3 Comorbidities in congenital heart disease patients and controls with ischemic heart disease diagnosed prior to, or coinciding, with index ischemic heart disease event.
Hypertension Diabetes mellitus Atrial fibrillation Heart failure CoHD = congenital heart disease.
CoHD % (n)
Controls % (n)
9.7 (27) 1.8 (5) 6.5 (18) 19.4 (54)
19.7 (36) 7.7 (14) 6.0 (11) 7.1 (13)
follow-up. However, the patients described by Roifman were slightly older and had a higher prevalence of conventional risk factors: hypertension was present in 45% of the aortic coarctation group and 16% of the ventricular septal defect group, and they had a much higher prevalence of diabetes (6%) compared to our finding of only 1.8%. However, neither study found any major or significant increase in the risk of IHD or AMI among patients with aortic coarctation as compared to patients with other CoHD diagnoses. In addition, we found that patients with aortic coarctation had the lowest relative increase in HR of AMI as compared to the other groups. Our data would thus add further to the notion that patients with aortic coarctation do not have a specific increase in the risk of developing coronary artery disease. We found the cumulative incidence of IHD to be higher in the birth cohort 1980–1989 than the birth cohort 1970–1979 for patients of the same age. A possible explanation for this is that patients in the earlier birth cohort may have had a higher early mortality rate and therefore a lower risk of developing and being diagnosed with IHD. This is illustrated in Fig. 1, which shows the cumulative incidence of IHD and a competing risk event (non-IHD-related death). Our group has previously reported data showing that the mortality risk has declined between 1970 and 1989 [6] but the present analysis suggests that the increased risk of IHD has not declined in a similar manner. Our study is the first large registry study to investigate the risk of IHD in children and young adults with CoHD and the first to compare this risk with a matched control population without CoHD. The strength of this study is its large scale: it includes almost all CoHD patients in Sweden born between 1970 and 1993, with minimal loss to follow-up. Our findings are clinically important because adults with CoHD now live longer and the CoHD population is growing and ageing. Fig. 1 shows that the cumulative incidence of IHD is consistently higher in CoHD patients compared to controls from an early age and increases more rapidly in CoHD patients from about age 18. We cannot deduce the exact mechanisms for IHD in our population as the use of anonymized data meant that individual medical records could not be accessed. We believe that the mechanisms for IHD in young CoHD patients are multifactorial. Previous surgical procedures and associated physiological responses might contribute to the development of ischemia. Many patients living with CoHD have reduced maximal oxygen uptake in combination with increased oxygen demand due to volume pressure overload; they are thereby exposed to myocardial ischemia, even in the presence of normal coronaries [25]. Further, many CoHD patients undergo several radiological investigations from a young age and are hence more exposed to radiation of the thorax, which might accelerate
Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120
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atherosclerosis [26]. Also, a sedentary lifestyle and the presence of conventional risk factors such as diabetes [27] and hypertension [28] in CoHD patients might contribute to the development of atherosclerosis and IHD. Our study on a relatively young cohort of CoHD patients shows that the risk of IHD is generally increased in CoHD patients independently of the complexity of the lesions. This might suggest considerations of more intense monitoring and lowered thresholds for treatment of conventional risk factors as well as timely and proper identification of disease-specific risk factors in CoHD patients. 5. Limitations As in all registry studies, there is a risk of misclassification of both CoHD and IHD diagnoses in our study. Some diagnoses of IHD might have been classified differently in the ICD-8, ICD-9, and ICD-10 versions. Further, diagnosis of IHD might be challenging in patients with CoHD due to the prevalence of ECG changes secondary to previous surgical procedures and due to a possible increase in highly sensitive biomarkers even in the absence of necrosis (e.g. because of heart failure or atrial fibrillation). Nonetheless, the diagnoses in the patient registers we used have been shown to have a high level of validity, from 85 to 95% [13], and even higher in the diagnosis of MI and angina pectoris [13, 29]. The validity of these diagnoses in CoHD patients has not been specifically studied. Both underdiagnosis and overdiagnosis might occur more in CoHD patients than in controls in the presence of the same symptoms. There is no universal definition of angina; even so, the proportion of AMI as a percentage of all IHD in this young population was similar for cases and controls, or about one in three, and accordingly it is unlikely that the differences that we found would have been due to non-specific chest pain being present to a larger extent in the CoHD group. One of the main limitations in our study is that outpatient diagnoses have only been registered since 2001, which could have led to underestimation of the true IHD incidence. We cannot rule out that there could be a number of patients with IHD who were diagnosed and followed only in the outpatient clinics. Although the loss to follow-up in registry studies is generally low, a small proportion of the patients in our study were lost to follow-up, for example by moving abroad. Since the patients were followed from birth, there were no comorbidities at baseline, and we could not perform a standard logistic regression analysis to control for risk factors. Also, there might have been an underestimation of comorbidities, both in the CoHD group and in controls, if the diagnosis of cardiovascular risk factors was established only in primary care. There could also be a potential detection bias in CoHD as these patients are more closely monitored in the health care setting as compared to healthy controls. However, we do not believe that this leads to increased IHD risk estimates as we study young patients with or without CoHD. Among such young patients, b 42 years old by design of our study, there are probably other, more plausible explanations, for the increased risk of IHD than atherosclerosis. Finally, we were unable to access individual medical records and have no information on smoking and family history of coronary artery disease. Also, the more intricate mechanisms behind each IHD or AMI diagnosis cannot be determined, nor whether the IHD was due to arteriosclerosis, embolism or a consequence of previous surgical procedures. 6. Conclusions This large registry study on children and young adults with CoHD in Sweden shows that CoHD patients have a 16.5 times greater risk of being diagnosed with IHD compared to controls. However, the absolute risk of IHD is low in both groups. Patients with severe nonconotruncal defects and patients with conotruncal defects had the highest relative risk, while patients with atrial septal defect and ventricular septal defect had the lowest risk. Patients with aortic coarctation do not have a
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specific increase in the risk of developing IHD or AMI. More studies on IHD in CoHD patients are needed to explore the exact mechanisms of IHD in this heterogeneous patient group. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.06.120. Funding The present study was supported by grants from the Swedish state (under the agreement between the Swedish government and the county councils concerning economic support of research and education of doctors, ALF-agreement, grants ALFGBG-427301 and ALFGBG-435211); grants from the Swedish Heart and Lung Foundation (2015-0438 and 2009-0724) and the Swedish Research Council (340-2013-5187 and 521-2013-4236). The funding sources of the present study had no role in the study design, data collection or analysis, data interpretation, or in writing of the report. Conflicts of interest None. References [1] B. Khoshnood, N. Lelong, L. Houyel, A.C. Thieulin, J.M. Jouannic, S. Magnier, et al., Prevalence, timing of diagnosis and mortality of newborns with congenital heart defects: a population-based study, Heart 98 (22) (2012) 1667–1673. [2] A.J. Marelli, A.S. Mackie, R. Ionescu-Ittu, E. Rahme, L. Pilote, Congenital heart disease in the general population: changing prevalence and age distribution, Circulation 115 (2) (2007) 163–172. [3] A.J. Marelli, J. Therrien, A.S. Mackie, R. Ionescu-Ittu, L. Pilote, Planning the specialized care of adult congenital heart disease patients: from numbers to guidelines; an epidemiologic approach, Am. Heart J. 157 (1) (2009) 1–8. [4] P. Moons, L. Bovijn, W. Budts, A. Belmans, M. Gewillig, Temporal trends in survival to adulthood among patients born with congenital heart disease from 1970 to 1992 in Belgium, Circulation 122 (22) (2010) 2264–2272. [5] M. Olsen, T.D. Christensen, L. Pedersen, S.P. Johnsen, V.E. Hjortdal, Late mortality among Danish patients with congenital heart defect, Am. J. Cardiol. 106 (9) (2010) 1322–1326. [6] Z. Mandalenakis, A. Rosengren, K. Skoglund, G. Lappas, P. Eriksson, M. Dellborg, Survivorship in children and young adults with congenital heart disease in Sweden, JAMA Intern Med. 177 (2) (2017) 224–230. [7] O. Tutarel, A. Kempny, R. Alonso-Gonzalez, R. Jabbour, W. Li, A. Uebing, et al., Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality, Eur. Heart J. 35 (11) (2014) 725–732. [8] S. Yalonetsky, E.M. Horlick, M.D. Osten, L.N. Benson, E.N. Oechslin, C.K. Silversides, Clinical characteristics of coronary artery disease in adults with congenital heart defects, Int. J. Cardiol. 164 (2) (2013) 217–220. [9] H. Sugiyama, E. Tsuda, H. Ohuchi, O. Yamada, I. Shiraishi, Chronological changes in stenosis of translocated coronary arteries on angiography after the arterial switch operation in children with transposition of the great arteries: comparison of myocardial scintigraphy and angiographic findings, Cardiol. Young (2015) 1–6. [10] W.C. Wasek, W. Samul, R. Ryczek, A. Skrobowski, Unique case of ST-segmentelevation myocardial infarction related to paradoxical embolization and simultaneous pulmonary embolization: clinical considerations on indications for patent foramen ovale closure in no-guidelines land, Circulation 131 (13) (2015) 1214–1223. [11] G. Giannakoulas, K. Dimopoulos, R. Engel, O. Goktekin, Z. Kucukdurmaz, M.A. Vatankulu, et al., Burden of coronary artery disease in adults with congenital heart disease and its relation to congenital and traditional heart risk factors, Am. J. Cardiol. 103 (10) (2009) 1445–1450. [12] P. Pillutla, K.D. Shetty, E. Foster, Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005, Am. Heart J. 158 (5) (2009) 874–879. [13] J.F. Ludvigsson, E. Andersson, A. Ekbom, M. Feychting, J.L. Kim, C. Reuterwall, et al., External review and validation of the Swedish national inpatient register, BMC Public Health 11 (2011) 450. [14] S. Liu, K.S. Joseph, W. Luo, J.A. Leon, S. Lisonkova, M. Van den Hof, et al., Effect of folic acid food fortification in Canada on congenital heart disease subtypes, Circulation 134 (9) (2016) 647–655. [15] L.D. Botto, A.E. Lin, T. Riehle-Colarusso, S. Malik, A. Correa, National Birth Defects Prevention S, Seeking causes: classifying and evaluating congenital heart defects in etiologic studies, Birth Defects Res. A Clin. Mol. Teratol. 79 (10) (2007) 714–727. [16] N. Oyen, G. Poulsen, H.A. Boyd, J. Wohlfahrt, P.K. Jensen, M. Melbye, National time trends in congenital heart defects, Denmark, 1977–2005, Am. Heart J. 157 (3) (2009) 467–473 (e1). [17] S. Liu, K.S. Joseph, S. Lisonkova, J. Rouleau, M. Van den Hof, R. Sauve, et al., Association between maternal chronic conditions and congenital heart defects: a population-based cohort study, Circulation 128 (6) (2013) 583–589.
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Please cite this article as: M. Fedchenko, et al., Ischemic heart disease in children and young adults with congenital heart disease in Sweden, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.120