Downloaded from http://heart.bmj.com/ on September 5, 2017 - Published by group.bmj.com
Heart Online First, published on September 4, 2017 as 10.1136/heartjnl-2017-311997 Editorial
Acquired cardiovascular disease in adult patients with congenital heart disease George Giannakoulas, Despoina Ntiloudi The adult congenital heart disease (ACHD) population is expanding and ageing. As survival rates of these patients continue to improve, acquired cardiac conditions, such as ischaemic cerebrovascular events and coronary artery disease (CAD), are likely to gain importance.1 However, limited information about the spectrum and the mechanisms of these conditions is available. With regard to stroke, patients with ACHD are at a low absolute, yet a relative high risk compared with the general population. A retrospective analysis of 29 638 patients from Quebec showed that 1 in 11 men and 1 in 15 women between 18 and 64 years of age had a history of a stroke.2 In Euro Heart Survey on ACHD, in which the inclusion of patients with more complex lesions was quite high, 4% of 4168 patients experienced a cerebrovascular accident or transient ischaemic attack (TIA).3 In the Swedish Patient Registry of congenital heart disease, 0.5% of patients experienced an ischaemic stroke.4 A very low incidence was also found by Bokma et al, who reported that 56 out of 6904 patients had a history of ischaemic stroke/TIA.5 However, it should be taken into account that although population-based studies are of high importance, there are limitations inherited with this type of studies, as some details in the medical records cannot be adequately accessed. Jensen et al showed that in a cohort of 98 patients with cyanotic ACHD, findings consistent with previous stroke diagnosed with a brain MRI were reported in 47% of patients, while only 21% had a known medical history of a stroke, indicating the significant under-reporting and the high prevalence of ‘silent’ cerebrovascular events in this population.6 Consequently, the incidence of stroke/TIA might be underestimated. The pathophysiological mechanisms of stroke/TIA are yet to be defined. In the cohort from Quebec, stroke was mainly predicted by a history of heart failure, diabetes mellitus and myocardial Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece Correspondence to Dr George Giannakoulas, Department of Cardiology, AHEPA University Hospital, Thessaloniki 54636, Greece; g.giannakoulas@gmail. com
infarction.2 Even though heart failure was the strongest predictor of stroke, it is difficult to identify and separate the effect of associated comorbidities, especially of atrial arrhythmias, on this outcome. In terms of the underlying ACHD defect, patients with severe and left-sided lesions were more likely to develop stroke during adulthood. In the Swedish Patient Registry, a consistency in risk factors was reported with the heart failure being the strongest predictor followed by arterial hypertension and atrial fibrillation.4 Patients with aortic coarctation, double inlet ventricle and atrial shunts had the highest risk of developing an ischaemic stroke. In the study of Bokma et al, previous shunt operations, residual/unclosed septal defects and left-sided mechanical valves were the independent predictive factors of ischaemic cerebrovascular disease.5 Consequently, in this large case–control study, only factors related with the underlying cardiac lesion were revealed as predictors of strokes, suggesting that the aetiology of ischaemic cerebrovascular events in patients with ACHD is mostly cardioembolic. What actions should physicians take when treating patients with ACHD who suffer from a cerebrovascular event? In the general population, given that atherosclerosis is one of the main causes of strokes, antiplatelet agents play a pivotal role in the therapeutic algorithm.3 However, Bokma et al demonstrated that the aetiology of ischaemic stroke/TIA might not always be atherosclerosis and therefore there seems to be a gap in the management of these patients. More data are, thus, required to define if the extrapolation of the guidelines for the general population to the patients with ACHD is proper or if anticoagulation should be administered in all or in selected cases. As far as CAD is concerned, it should not escape us that we need to pay more attention to prevention, better diagnosis and management of coronary atherosclerosis in our patients with ACHD. The incidence of obstructive atherosclerotic CAD in a cohort of 12 124 patients with ACHD, which was reviewed retrospectively, was 1%,7 while in a study of 250 patients (mean age 51±15 years) who had undergone selective coronary angiography for other reasons than suspicion Giannakoulas G, Ntiloudi D. Heart Month 2017 Vol 0 No 0
of CAD, 9.2% were reported to have significant CAD, which was defined as the presence of at least one lesion with diameter stenosis more than 50% in a major vessel.8 Furthermore, given that myocardial infarction was the leading cause of death in adults with non-cyanotic lesions after 1990 in USA,9 CAD should always be taken into account in the differential diagnosis of chest pain. CAD in ACHD can be an outcome of congenital coronary artery abnormalities, previous surgical procedures such as arterial switch operation in patients with transposition of the great arteries, compression of the left coronary ostium by a dilated pulmonary artery in patients with Eisenmenger syndrome and acquired atherosclerotic disease.10 As patients with congenital heart disease age, the traditional cardiovascular risk factors contribute to the development of atherosclerotic disease. Prevalence of arterial hypertension in these patients is reported to be between 30% and 50%. Systemic screening of dyslipidaemia, smoking history and obesity should be performed and a healthy lifestyle should be pursued in all our patients with ACHD. Even though smoking is not that popular compared with the general population, it still predicts CAD in ACHD as it was demonstrated by Bokma et al.5 Obesity prevalence in ACHD seems to be higher than expected, partially because, in the past, these patients were not encouraged to exercise. Results from CONCOR are in line with the results of a study from the Royal Brompton Hospital, where systemic arterial hypertension and hyperlipidaemia were revealed as strong predictors of CAD.5 8 Even though in a recent study from the Swedish registry patients with congenital heart disease and CAD had less common a history of hypertension or diabetes mellitus compared with controls, it should be noted that this study refers to children and young adults (mean age 9.6±11.3 years).11 Therefore, screening for traditional cardiovascular risk factors in the ageing ACHD population is as important as in the general population. Cyanosis is believed to play a protective role in CAD. Indeed, JK Perloff was a pioneer in the experimental work in the coronary circulation of patients with cyanosis.12 In a study with coronary arteriograms and necropsy specimens, extramural coronary arteries were found to respond to endothelial vasodilator substances (nitric oxide and prostaglandins) with mild to moderate dilation and then dilate further due to medial structural abnormalities. Characteristics of patients with cyanosis 1
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from http://heart.bmj.com/ on September 5, 2017 - Published by group.bmj.com
Editorial Table 1 Pathophysiology of acquired cardiovascular disease in congenital heart disease Acquired cardiovascular diseases in ACHD Stroke
CAD
ACHD-related factors
Non-ACHD-related factors
ACHD-related factors
Non-ACHD-related factors
►► Previous shunt operations ►► Residual/unclosed septal defects ►► Left-sided mechanical valves ►► Arrhythmias ►► Endocarditis ►► Hypoxaemia ►► Secondary erythrocytosis ►► Iron deficiency ►► Associated syndromes ►► Heart failure
►► Age ►► Heart failure ►► Myocardial infarction ►► Diabetes mellitus ►► Arterial hypertension ►► Arrhythmias
►► Congenital coronary artery abnormalities ►► Previous surgical procedures ►► Compression of the left coronary ostium ►► Cyanosis
►► Age ►► Arterial hypertension ►► Hypercholesterolaemia ►► Smoking ►► Obesity
ACHD, adult congenital heart disease; CAD, coronary artery disease,
such as hypocholesterolaemia, hypoxaemia, upregulation of nitric oxide, hyperbilirubinaemia and low platelet counts were likely to be the contributors of the low incidence of coronary atherosclerosis in cyanotic ACHD. This was also supported by the study of Giannakoulas et al, in which no patient with cyanosis had CAD,8 as well as a case–control study where atherosclerosis disease risk and, in specific, carotid intima-media thickness was decreased in 54 patients with cyanosis with ACHD (mean age 38 years).13 Lower blood pressure, lower total cholesterol levels, higher bilirubin levels and lower thrombocyte levels seemed to contribute to this outcome. However, there are some reported cases where CAD coexists in patients with cyanosis.7 14 Unfortunately, the design of the study of Bokma et al by congenital heart defect subgroup matching patients to controls did not permit the investigation of the effect of ACHD severity and cyanosis in CAD.5 Experimental work is required to identify the exact effect of cyanosis on the coronary vascular bed, especially in the long term, as the continually evolving surveillance of patients with cyanosis has led to the increase of their life expectancy. As the patients with ACHD age, the incidence of acquired cardiovascular accidents such as stroke and CAD is likely to increase. Bokma et al showed that the pathophysiology of stroke and CAD in the ACHD population might be different (table 1). The roots of these problems either related to ACHD per se or to traditional
2
cardiovascular risk factors should be thoroughly sought and aggressively addressed in order to improve the survival prospects in this heterogeneous population. Contributors Both authors have participated in the work and have reviewed and agreed with the content of the article and with its submission. Competing interests None declared. Provenance and peer review Commissioned; internally peer reviewed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
To cite Giannakoulas G, Ntiloudi D. Heart Published Online First: [please include Day Month Year]. doi:10.1136/heartjnl-2017-311997
►► http://dx.doi.org/10.1136/heartjnl-2017-311620
Heart 2017;0:1–2. doi:10.1136/heartjnl-2017-311997
References
1 Tutarel O, Kempny A, Alonso-Gonzalez R, 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 2014;35:725–32. 2 Lanz J, Brophy JM, Therrien J, et al. Stroke in adults with congenital heart disease: incidence, cumulative risk, and predictors. Circulation 2015;132:2385–94. 3 Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity
and mortality in a 5 year follow-up period. The Euro heart survey on adult congenital heart disease. Eur Heart J 2005;26:2325–33. 4 Mandalenakis Z, Rosengren A, Lappas G, et al. Ischemic stroke in children and young adults with congenital heart disease. J Am Heart Assoc 2016;5:e003071. 5 Bokma JP, Zegstroo I, Kuijpers JM, et al. Factors associated with coronary artery disease and stroke in adults with congenital heart disease. Heart 2017:heartjnl-2017-311620. 6 Jensen AS, Idorn L, Thomsen C, et al. Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease. Heart 2015;101:1540–6. 7 Yalonetsky S, Horlick EM, Osten MD, et al. Clinical characteristics of coronary artery disease in adults with congenital heart defects. Int J Cardiol 2013;164:217–20. 8 Giannakoulas G, Dimopoulos K, Engel R, 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 2009;103:1445–50. 9 Pillutla P, Shetty KD, Foster E. Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005. Am Heart J 2009;158:874–9. 10 Tutarel O. Acquired heart conditions in adults with congenital heart disease: a growing problem. Heart 2014;100:1317–21. 11 Fedchenko M, Mandalenakis Z, Rosengren A, et al. Ischemic heart disease in children and young adults with congenital heart disease in Sweden. Int J Cardiol 2017 (Epub ahead of print: 5 Feb 2017). 12. Perloff JK. The coronary circulation in cyanotic congenital heart disease. Int J Cardiol 2004;97(Suppl 1):79–86. 13 Duffels MG, Mulder KM, Trip MD, et al. Atherosclerosis in patients with cyanotic congenital heart disease. Circ J 2010;74:1436–41. 14 Abraham D, Freeman LJ, Lewis C, et al. Coronary artery disease in Eisenmenger’s syndrome – rare but not to be forgotten. Int J Cardiol 2016;203:276–7.
Giannakoulas G, Ntiloudi D. Heart Month 2017 Vol 0 No 0
Downloaded from http://heart.bmj.com/ on September 5, 2017 - Published by group.bmj.com
Acquired cardiovascular disease in adult patients with congenital heart disease George Giannakoulas and Despoina Ntiloudi Heart published online September 4, 2017
Updated information and services can be found at: http://heart.bmj.com/content/early/2017/09/04/heartjnl-2017-311997
These include:
References Email alerting service
This article cites 12 articles, 4 of which you can access for free at: http://heart.bmj.com/content/early/2017/09/04/heartjnl-2017-311997 #BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Heart Online First, published on September 4, 2017 as 10.1136/heartjnl-2017-311997 Editorial
Acquired cardiovascular disease in adult patients with congenital heart disease George Giannakoulas, Despoina Ntiloudi The adult congenital heart disease (ACHD) population is expanding and ageing. As survival rates of these patients continue to improve, acquired cardiac conditions, such as ischaemic cerebrovascular events and coronary artery disease (CAD), are likely to gain importance.1 However, limited information about the spectrum and the mechanisms of these conditions is available. With regard to stroke, patients with ACHD are at a low absolute, yet a relative high risk compared with the general population. A retrospective analysis of 29 638 patients from Quebec showed that 1 in 11 men and 1 in 15 women between 18 and 64 years of age had a history of a stroke.2 In Euro Heart Survey on ACHD, in which the inclusion of patients with more complex lesions was quite high, 4% of 4168 patients experienced a cerebrovascular accident or transient ischaemic attack (TIA).3 In the Swedish Patient Registry of congenital heart disease, 0.5% of patients experienced an ischaemic stroke.4 A very low incidence was also found by Bokma et al, who reported that 56 out of 6904 patients had a history of ischaemic stroke/TIA.5 However, it should be taken into account that although population-based studies are of high importance, there are limitations inherited with this type of studies, as some details in the medical records cannot be adequately accessed. Jensen et al showed that in a cohort of 98 patients with cyanotic ACHD, findings consistent with previous stroke diagnosed with a brain MRI were reported in 47% of patients, while only 21% had a known medical history of a stroke, indicating the significant under-reporting and the high prevalence of ‘silent’ cerebrovascular events in this population.6 Consequently, the incidence of stroke/TIA might be underestimated. The pathophysiological mechanisms of stroke/TIA are yet to be defined. In the cohort from Quebec, stroke was mainly predicted by a history of heart failure, diabetes mellitus and myocardial Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece Correspondence to Dr George Giannakoulas, Department of Cardiology, AHEPA University Hospital, Thessaloniki 54636, Greece; g.giannakoulas@gmail. com
infarction.2 Even though heart failure was the strongest predictor of stroke, it is difficult to identify and separate the effect of associated comorbidities, especially of atrial arrhythmias, on this outcome. In terms of the underlying ACHD defect, patients with severe and left-sided lesions were more likely to develop stroke during adulthood. In the Swedish Patient Registry, a consistency in risk factors was reported with the heart failure being the strongest predictor followed by arterial hypertension and atrial fibrillation.4 Patients with aortic coarctation, double inlet ventricle and atrial shunts had the highest risk of developing an ischaemic stroke. In the study of Bokma et al, previous shunt operations, residual/unclosed septal defects and left-sided mechanical valves were the independent predictive factors of ischaemic cerebrovascular disease.5 Consequently, in this large case–control study, only factors related with the underlying cardiac lesion were revealed as predictors of strokes, suggesting that the aetiology of ischaemic cerebrovascular events in patients with ACHD is mostly cardioembolic. What actions should physicians take when treating patients with ACHD who suffer from a cerebrovascular event? In the general population, given that atherosclerosis is one of the main causes of strokes, antiplatelet agents play a pivotal role in the therapeutic algorithm.3 However, Bokma et al demonstrated that the aetiology of ischaemic stroke/TIA might not always be atherosclerosis and therefore there seems to be a gap in the management of these patients. More data are, thus, required to define if the extrapolation of the guidelines for the general population to the patients with ACHD is proper or if anticoagulation should be administered in all or in selected cases. As far as CAD is concerned, it should not escape us that we need to pay more attention to prevention, better diagnosis and management of coronary atherosclerosis in our patients with ACHD. The incidence of obstructive atherosclerotic CAD in a cohort of 12 124 patients with ACHD, which was reviewed retrospectively, was 1%,7 while in a study of 250 patients (mean age 51±15 years) who had undergone selective coronary angiography for other reasons than suspicion Giannakoulas G, Ntiloudi D. Heart Month 2017 Vol 0 No 0
of CAD, 9.2% were reported to have significant CAD, which was defined as the presence of at least one lesion with diameter stenosis more than 50% in a major vessel.8 Furthermore, given that myocardial infarction was the leading cause of death in adults with non-cyanotic lesions after 1990 in USA,9 CAD should always be taken into account in the differential diagnosis of chest pain. CAD in ACHD can be an outcome of congenital coronary artery abnormalities, previous surgical procedures such as arterial switch operation in patients with transposition of the great arteries, compression of the left coronary ostium by a dilated pulmonary artery in patients with Eisenmenger syndrome and acquired atherosclerotic disease.10 As patients with congenital heart disease age, the traditional cardiovascular risk factors contribute to the development of atherosclerotic disease. Prevalence of arterial hypertension in these patients is reported to be between 30% and 50%. Systemic screening of dyslipidaemia, smoking history and obesity should be performed and a healthy lifestyle should be pursued in all our patients with ACHD. Even though smoking is not that popular compared with the general population, it still predicts CAD in ACHD as it was demonstrated by Bokma et al.5 Obesity prevalence in ACHD seems to be higher than expected, partially because, in the past, these patients were not encouraged to exercise. Results from CONCOR are in line with the results of a study from the Royal Brompton Hospital, where systemic arterial hypertension and hyperlipidaemia were revealed as strong predictors of CAD.5 8 Even though in a recent study from the Swedish registry patients with congenital heart disease and CAD had less common a history of hypertension or diabetes mellitus compared with controls, it should be noted that this study refers to children and young adults (mean age 9.6±11.3 years).11 Therefore, screening for traditional cardiovascular risk factors in the ageing ACHD population is as important as in the general population. Cyanosis is believed to play a protective role in CAD. Indeed, JK Perloff was a pioneer in the experimental work in the coronary circulation of patients with cyanosis.12 In a study with coronary arteriograms and necropsy specimens, extramural coronary arteries were found to respond to endothelial vasodilator substances (nitric oxide and prostaglandins) with mild to moderate dilation and then dilate further due to medial structural abnormalities. Characteristics of patients with cyanosis 1
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from http://heart.bmj.com/ on September 5, 2017 - Published by group.bmj.com
Editorial Table 1 Pathophysiology of acquired cardiovascular disease in congenital heart disease Acquired cardiovascular diseases in ACHD Stroke
CAD
ACHD-related factors
Non-ACHD-related factors
ACHD-related factors
Non-ACHD-related factors
►► Previous shunt operations ►► Residual/unclosed septal defects ►► Left-sided mechanical valves ►► Arrhythmias ►► Endocarditis ►► Hypoxaemia ►► Secondary erythrocytosis ►► Iron deficiency ►► Associated syndromes ►► Heart failure
►► Age ►► Heart failure ►► Myocardial infarction ►► Diabetes mellitus ►► Arterial hypertension ►► Arrhythmias
►► Congenital coronary artery abnormalities ►► Previous surgical procedures ►► Compression of the left coronary ostium ►► Cyanosis
►► Age ►► Arterial hypertension ►► Hypercholesterolaemia ►► Smoking ►► Obesity
ACHD, adult congenital heart disease; CAD, coronary artery disease,
such as hypocholesterolaemia, hypoxaemia, upregulation of nitric oxide, hyperbilirubinaemia and low platelet counts were likely to be the contributors of the low incidence of coronary atherosclerosis in cyanotic ACHD. This was also supported by the study of Giannakoulas et al, in which no patient with cyanosis had CAD,8 as well as a case–control study where atherosclerosis disease risk and, in specific, carotid intima-media thickness was decreased in 54 patients with cyanosis with ACHD (mean age 38 years).13 Lower blood pressure, lower total cholesterol levels, higher bilirubin levels and lower thrombocyte levels seemed to contribute to this outcome. However, there are some reported cases where CAD coexists in patients with cyanosis.7 14 Unfortunately, the design of the study of Bokma et al by congenital heart defect subgroup matching patients to controls did not permit the investigation of the effect of ACHD severity and cyanosis in CAD.5 Experimental work is required to identify the exact effect of cyanosis on the coronary vascular bed, especially in the long term, as the continually evolving surveillance of patients with cyanosis has led to the increase of their life expectancy. As the patients with ACHD age, the incidence of acquired cardiovascular accidents such as stroke and CAD is likely to increase. Bokma et al showed that the pathophysiology of stroke and CAD in the ACHD population might be different (table 1). The roots of these problems either related to ACHD per se or to traditional
2
cardiovascular risk factors should be thoroughly sought and aggressively addressed in order to improve the survival prospects in this heterogeneous population. Contributors Both authors have participated in the work and have reviewed and agreed with the content of the article and with its submission. Competing interests None declared. Provenance and peer review Commissioned; internally peer reviewed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
To cite Giannakoulas G, Ntiloudi D. Heart Published Online First: [please include Day Month Year]. doi:10.1136/heartjnl-2017-311997
►► http://dx.doi.org/10.1136/heartjnl-2017-311620
Heart 2017;0:1–2. doi:10.1136/heartjnl-2017-311997
References
1 Tutarel O, Kempny A, Alonso-Gonzalez R, 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 2014;35:725–32. 2 Lanz J, Brophy JM, Therrien J, et al. Stroke in adults with congenital heart disease: incidence, cumulative risk, and predictors. Circulation 2015;132:2385–94. 3 Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity
and mortality in a 5 year follow-up period. The Euro heart survey on adult congenital heart disease. Eur Heart J 2005;26:2325–33. 4 Mandalenakis Z, Rosengren A, Lappas G, et al. Ischemic stroke in children and young adults with congenital heart disease. J Am Heart Assoc 2016;5:e003071. 5 Bokma JP, Zegstroo I, Kuijpers JM, et al. Factors associated with coronary artery disease and stroke in adults with congenital heart disease. Heart 2017:heartjnl-2017-311620. 6 Jensen AS, Idorn L, Thomsen C, et al. Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease. Heart 2015;101:1540–6. 7 Yalonetsky S, Horlick EM, Osten MD, et al. Clinical characteristics of coronary artery disease in adults with congenital heart defects. Int J Cardiol 2013;164:217–20. 8 Giannakoulas G, Dimopoulos K, Engel R, 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 2009;103:1445–50. 9 Pillutla P, Shetty KD, Foster E. Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005. Am Heart J 2009;158:874–9. 10 Tutarel O. Acquired heart conditions in adults with congenital heart disease: a growing problem. Heart 2014;100:1317–21. 11 Fedchenko M, Mandalenakis Z, Rosengren A, et al. Ischemic heart disease in children and young adults with congenital heart disease in Sweden. Int J Cardiol 2017 (Epub ahead of print: 5 Feb 2017). 12. Perloff JK. The coronary circulation in cyanotic congenital heart disease. Int J Cardiol 2004;97(Suppl 1):79–86. 13 Duffels MG, Mulder KM, Trip MD, et al. Atherosclerosis in patients with cyanotic congenital heart disease. Circ J 2010;74:1436–41. 14 Abraham D, Freeman LJ, Lewis C, et al. Coronary artery disease in Eisenmenger’s syndrome – rare but not to be forgotten. Int J Cardiol 2016;203:276–7.
Giannakoulas G, Ntiloudi D. Heart Month 2017 Vol 0 No 0
Downloaded from http://heart.bmj.com/ on September 5, 2017 - Published by group.bmj.com
Acquired cardiovascular disease in adult patients with congenital heart disease George Giannakoulas and Despoina Ntiloudi Heart published online September 4, 2017
Updated information and services can be found at: http://heart.bmj.com/content/early/2017/09/04/heartjnl-2017-311997
These include:
References Email alerting service
This article cites 12 articles, 4 of which you can access for free at: http://heart.bmj.com/content/early/2017/09/04/heartjnl-2017-311997 #BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
