UNIVERSITY NEWS
Einthoven Dissertatie Cardiologie Prijzen 2000 For the twelfth time in a row, the Dutch Cardiac Society (NVVC), the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the sponsor, Sanofi Synthelabo, are supporting the competition for the best three PhD theses published last year on a cardiovascular subject. From now one, the prizes carry the prizes do not carry the name of the sponsor, but of one of the great men in the history of cardiology: Willem Einthoven (1860-1927), the pioneer ofthe human ECG. The jury, consisting of representatives of the NVVC, the ICIN, and Sanofi Synthelabo, were given 14 dissertations to review. The jury members were impressed and pleased by the scientific quality of the work of the young doctors. It was not easy to decide upon the winners. The three nominees will present their work at the spring meeting of the NVVC, which will be held in Scheveningen on 27 April 2001. The winner of the first, second and third prize will be chosen by the audience. Summaries ofthe three nominated PhD theses are given below. C Prof. Dr. H.J.J. Wellens, Chairman of the Jury.
lescents. However, ascending aortic dilation is not an infrequent finding in Marfan adolescents. Prophylactic repair ofascending Doctoral candidate: Maarten Groenink, Promotors: Prof. Dr. E.E. aortic aneurysms (Bentall provan der Wall, Prof. Dr. A. de Roos, cedure) has greatly increased life expectancy (approximately from 40 Co-promotor: Dr. B.J.M. Mulder years to 60 years) in Marfin patients. New surgical techniques are conSurvival In Marfan syndrome The diversity of pathology caused stantly emerging, including the use by Marfan syndrome, an autosomal of cryopreserved homografts for dominantly inherited disorder of aortic repair. We showed that the connective tissue, has resulted in a mechanical properties (breaking multi-disciplinary clinical approach stress, elasticity) of aortic homografrs regarding diagnosis and treatment. are not influenced by standard Cardiologists and cardiovascular cryopreservation techniques. Much surgeons, however, play the most ofthe research performed in the last important role in the management decades has focused on the optimal of Marfan patients, because prog- timing for prophylactic repair ofthe nosis is greatly determined aorta, which is greatly determined by cardiovascular complications, by aneurysm size and expansion rate. especially aortic dissection and In our studies, ten-year survival was rupture. The occurrence of aortic shown to be satisfactory when dissection in Marfan patients is recently formulated guidelines for favourably influenced by treatment prophylactic repair were applied to with f-adrenergic blocking agents. a cohort of 125 patients who visited This effect has been attributed to a the Academic Medical Centre in decrease in contractile force (dp/dt) Amsterdam in the past 14 years. of the heart, reduction in blood However, a small group ofpatients pressure and a decrease in fatiguing developed unforeseen aortic disstress cycles on the aortic wall (by a section. This may partly be due to decrease in heart rate). The techniques used to monitor aortic defective aortic wall in Marfan aneurysm size, as illustrated by a patients seems to require some study in which we compared echo'wear-and-tear' before aortic dis- cardiography and magnetic section occurs as this complication, resonance imaging (MRI) to assess which is often lethal, is rarely aneurysm morphology in Marfan observed in children and ado- patients. Due to the inclusion ofthe
The Marfan aorta: morphology, growth and functional properties
Netherands Heart Joumal, Volume 9, Number 1, Aprl 2001
sinus of Valsalva, these aneurysms are often asymmetrically shaped. Hence, assessment of these aneurysms may require a threedimensional approach.
Diagnosis Early diagnosis is ofmajor importance for both therapy and follow-up. Because of the vast variability in phenotype and symptoms, which develop gradually during childhood and adolescence, this is a major challenge for many physicians, especially paediatric cardiologists. 'New' Marfan patients are emerging constantly. The number of new mutations has been estimated to be up to 30% ofall known patients. Lack of ectopia lentis has been associated with poor survival, probably because patients were not recognised in time. For the most important features, clinical imaging is necessary and even then diagnosis is hampered by the variability of signs in a Marfan screening population. Because ofthis variability, we proposed a new nomogram for 'normal' aortic root size based on our own screening popu-lation of 250 children and adole-scents suspected of Marfan syndrome. Add-itionally, we used echocardiography to evaluate individual aortic root growth in this population as an early sign ofMarfan syndrome. It was shown that in many patients, aortic root growth sug59
University news
gested Marfan syndrome before the aortic root was sufficiently dilated to contribute to the diagnosis as a major critenon. In young adults, we found that the most powerful indicator of Marfan syndrome is the presence of lumbosacral dural ectasia, as can easily be diagnosed by MRI.
children with Marfan syndrome has yet to be investigated. These investigations are now being conducted by Drs. G.J. Nollen, who is supported by the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the Netherlands Heart Foundation. -
Risk stratffication From survival studies (and our own clinical experience) we concluded that some Marfan patients develop aortic complications, that are not limited to the ascending aorta irrespective of known risk factors. Decreased aortic elasticity was considered as an additional functional risk factor for aortic dissection. Firstly, we determined breaking stress of the normal aorta and showed that aortic breaking stress was correlated with aortic elastic properties in vitro. Then we assessed elastic properties throughout the aorta by MRI in Marfan patients with a normal-sized aorta distal to the aortic root and matched controls. It was shown that Marfan patients already exhibit reduced aortic elasticity in these undilated aortic tracts. In another study it was shown that treatment with [Bblocking agents increased aortic elasticity in Marfan patients.
New Insights In the electrical treat-nent of atrial flbrillation: the atrial defibrillator
Future perspectives
Follow-up of the Marfan patients who underwent MRI for detection of reduced elasticity will be performed. In due course, the value of aortic elasticity on aortic complications and mortality in Marfan patients will become clear. Aortic elasticity of Marfan patients who underwent prophylactic repair of the aortic root and the occurrence or proximal coronary dilation in these patients are still to be investigated. Assessment of aortic root elasticity seems to require a complicated three-dimensional approach, for which MRI, continuously measured blood pressure (non-invasively by Finapress), and finite element reconstruction are necessary. Moreover, the value of dural ectasia as a sign for Marfan syndrome in 60
Doctoral candidate: Dr. C. Timmermans, Promotors: Prof. Dr. H.J.J. Wellens, Co-promotor: Dr. L-M. Rodriguez
Antiarrhythmic drugs and external cardioversion are the primary modes of treatment of patients with atrial fibrillation. Because of the limited efficacy and safety of antiarrhythmic drugs and repeated hospitalisations for external cardioversion, requiring general anaesthesia, several nonpharmacological options have been developed, especially for patients with recurrent atrial fibrillation. One of them, the implantable atrial defibrillator, has only recently been introduced. In the thesis, the first experience with the atrial defibrillator is described. The atrial defibrillator is a pectorally implanted device connected to right atrial and coronary sinus defibrillation leads and a bipolar ventricular pacing lead (figure 1). Biphasic shocks are programmable up to 6 J. The device uses a dual algorithm to detect atrial fibrillation and delivers R-wave synchronous defibrillation shocks to convert atrial fibrillation to sinus rhythm. It is also able to pace the ventricle in case ofpostshock bradycardia. The device can be programmed in an automatic mode with periodic activation of the device for AF detection and defibrillation. The patient-activated mode allows the patient to activate the device with a magnet. In a prospective, worldwide, multicentre study, the device was implanted in patients without structural heart disease and was able to
Figure 1. Chest x-ray showing the atrial defibrillator connected with a right atrium defibrillation lead, a coronary sinus defibrillation lead, and a right ventricular bipolar lead.
restore sinus rhythm promptly and safely with low amounts of energy. In these patients, the frequency of long-lasting atrial fibrillation episodes, which were treated under physician observation, decreased. However, the number and duration ofshort-lasting, nontreated episodes did not change during a 20-month study period. Ambulatory therapy with the atrial defibrillator is feasible as the device can terminate most episodes of atrial fibrillation in the patient's ambient setting without induction of ventricular proarrhythmia. Interestingly, in the majority of the patients, atrial fibrillation can be treated with the device without sedation. The need for sedation is related to the number of shocks delivered to treat an atrial fibrillation episode. Although some shocks initially fail to convert atrial fibrinlation to sinus rhythm, reinitiation of atrial fibrillation within minutes after a successful cardioversion (IRAF) is the most frequent cause of the delivery of additional shocks. Because atrial fibrillation mainly occurs in patients with structural heart disease, the feasibility of the atrial defibrillator was also evaluated in a patient with congenital heart disease. The device proved to be a valid treatment option in this patient crippled by the arrhythmia. Netherlands Heart Joumal, Volume 9, Number 1, April 2001
University news
Whether an implantable atrial defibrillator improves quality of life and is cost-effective needs to be studied. U
Strategles of coronary reperfusion In acute myocardial infarction for patients admitted to hospitals without angloplasty facilities
Doctoral candidate: Dr. A.J.M. Oude Ophuis, Promotors: Prof. Dr. F.W.H.M. Bar, Prof. Dr. H.J.J. Wellens, Co-promotor: Dr. F. Vermeer
At present, two reperfusion techniques have proven their efficacy in the treatment of acute myocardial infarction; administration of a fibrinolytic agent and mechanical reopening of the occluded vessel followed by percutaneous transluminal coronary angioplasty (PTCA). Rescue PTCA after failed thrombolysis is likely to be beneficial, but definite proof is not available. So far, angioplasty in acute myocardial infarction has primarily been studied and practised in patients who were admitted directly to a PTCA centre. However, the majority of patients with an acute myocardial infarction present to hospitals without PTCA facilities (85% of the patients in the Netherlands). The purpose of this thesis is to compare three strategies of management of extensive acute myocardial infarction; a) thrombolytic therapy, b) thrombolytic therapy followed by acute coronary angiography and (if indicated) Table 2. Where to go from here; prehospital triage?
Netherlands Heart Joumal, Volume 9, Number 1, Aprl 2001
Table 1. LIMI study: Clinical course during one year follow-up. Thrombolysis Thrombolysis + rescue PTCA N N Number of patients 75 74 Deceased 6 (5) 7 (6) Thrombolic stroke 1 (1) 2 (1) Haemorrhagic stroke 1 (1) 2 (2) Recurrent infarction 9 (7) 5 (4) Late PTCA/CABG 29 (23) 24 (17) Recurrent 10 (6) 9 (5) ischaemia only* None of the above 33 (48) 38 (44)
Prlmary PTCA N 75 9 2 0 4 10 10
(5) (2) (0) (1) (6) (6)
47 (58)
Data are of one year follow-up. Between brackets data conceming 42 days follow-up. *Recurrent ischaemia without infarction and not followed by intervention (PTCA/CABG).
PTCA, and c) primary PTCA, in patients who are admitted to a hospital without angioplasty facilities. The questions to be answered in this thesis were threefold. The first important clinical question was whether the angiographic and clinical outcome differs between rescue and primary PTCA?P Secondly, can noninvasive parameters of reperfusion be of help in selecting patients for acute coronary angiography and subsequent coronary angioplasty? Thirdly, do patients who are admitted to a centre without PTCA facilities benefit from early transfer to a PTCA centre for rescue
rescue angioplasty or primary angio-
plasty and can this be performedwith a favourable relation between cost and effect? Conclusions
1. The clinical and angiographic outcome for patients with acute myocardial infarction with angiographically proven inadequate coronary flow is similar for early rescue PTCA and primary PTCA. 2. Reperfusion parameters are of help in identifying patients with acute myocardial infarction with open coronary arteries in which subsequent angioplasty is not necessary. TIMI 3 flow cannot reliably be discriminated from TIMI 2 flow. However, the prognosis of patients with acute
myocardial infarction with positive criteria of reperfusion is excellent. 3. Acute transfer of patients with extensive acute myocardial infarction from a hospital without angioplasty facilities to a
hospital with angioplasty facilities is safe and at least in the Maastricht setting feasible and can be done in a therapeutically acceptable time window. Transferring patients to a PTCA centre may improve clinical outcome but at significant cost (table 1). The extra cost per additional MACE free survivor in comparison with thrombolytic treatment seems most favourable for primary PTCA. The treatment with 'thrombolysis only' remains the best alternative in an environment of limited resources. Where to go from here? (table 2) For slideshow: www.doctoroudeophuis.com
61
Einthoven Dissertatie Cardiologie Prijzen 2000 For the twelfth time in a row, the Dutch Cardiac Society (NVVC), the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the sponsor, Sanofi Synthelabo, are supporting the competition for the best three PhD theses published last year on a cardiovascular subject. From now one, the prizes carry the prizes do not carry the name of the sponsor, but of one of the great men in the history of cardiology: Willem Einthoven (1860-1927), the pioneer ofthe human ECG. The jury, consisting of representatives of the NVVC, the ICIN, and Sanofi Synthelabo, were given 14 dissertations to review. The jury members were impressed and pleased by the scientific quality of the work of the young doctors. It was not easy to decide upon the winners. The three nominees will present their work at the spring meeting of the NVVC, which will be held in Scheveningen on 27 April 2001. The winner of the first, second and third prize will be chosen by the audience. Summaries ofthe three nominated PhD theses are given below. C Prof. Dr. H.J.J. Wellens, Chairman of the Jury.
lescents. However, ascending aortic dilation is not an infrequent finding in Marfan adolescents. Prophylactic repair ofascending Doctoral candidate: Maarten Groenink, Promotors: Prof. Dr. E.E. aortic aneurysms (Bentall provan der Wall, Prof. Dr. A. de Roos, cedure) has greatly increased life expectancy (approximately from 40 Co-promotor: Dr. B.J.M. Mulder years to 60 years) in Marfin patients. New surgical techniques are conSurvival In Marfan syndrome The diversity of pathology caused stantly emerging, including the use by Marfan syndrome, an autosomal of cryopreserved homografts for dominantly inherited disorder of aortic repair. We showed that the connective tissue, has resulted in a mechanical properties (breaking multi-disciplinary clinical approach stress, elasticity) of aortic homografrs regarding diagnosis and treatment. are not influenced by standard Cardiologists and cardiovascular cryopreservation techniques. Much surgeons, however, play the most ofthe research performed in the last important role in the management decades has focused on the optimal of Marfan patients, because prog- timing for prophylactic repair ofthe nosis is greatly determined aorta, which is greatly determined by cardiovascular complications, by aneurysm size and expansion rate. especially aortic dissection and In our studies, ten-year survival was rupture. The occurrence of aortic shown to be satisfactory when dissection in Marfan patients is recently formulated guidelines for favourably influenced by treatment prophylactic repair were applied to with f-adrenergic blocking agents. a cohort of 125 patients who visited This effect has been attributed to a the Academic Medical Centre in decrease in contractile force (dp/dt) Amsterdam in the past 14 years. of the heart, reduction in blood However, a small group ofpatients pressure and a decrease in fatiguing developed unforeseen aortic disstress cycles on the aortic wall (by a section. This may partly be due to decrease in heart rate). The techniques used to monitor aortic defective aortic wall in Marfan aneurysm size, as illustrated by a patients seems to require some study in which we compared echo'wear-and-tear' before aortic dis- cardiography and magnetic section occurs as this complication, resonance imaging (MRI) to assess which is often lethal, is rarely aneurysm morphology in Marfan observed in children and ado- patients. Due to the inclusion ofthe
The Marfan aorta: morphology, growth and functional properties
Netherands Heart Joumal, Volume 9, Number 1, Aprl 2001
sinus of Valsalva, these aneurysms are often asymmetrically shaped. Hence, assessment of these aneurysms may require a threedimensional approach.
Diagnosis Early diagnosis is ofmajor importance for both therapy and follow-up. Because of the vast variability in phenotype and symptoms, which develop gradually during childhood and adolescence, this is a major challenge for many physicians, especially paediatric cardiologists. 'New' Marfan patients are emerging constantly. The number of new mutations has been estimated to be up to 30% ofall known patients. Lack of ectopia lentis has been associated with poor survival, probably because patients were not recognised in time. For the most important features, clinical imaging is necessary and even then diagnosis is hampered by the variability of signs in a Marfan screening population. Because ofthis variability, we proposed a new nomogram for 'normal' aortic root size based on our own screening popu-lation of 250 children and adole-scents suspected of Marfan syndrome. Add-itionally, we used echocardiography to evaluate individual aortic root growth in this population as an early sign ofMarfan syndrome. It was shown that in many patients, aortic root growth sug59
University news
gested Marfan syndrome before the aortic root was sufficiently dilated to contribute to the diagnosis as a major critenon. In young adults, we found that the most powerful indicator of Marfan syndrome is the presence of lumbosacral dural ectasia, as can easily be diagnosed by MRI.
children with Marfan syndrome has yet to be investigated. These investigations are now being conducted by Drs. G.J. Nollen, who is supported by the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the Netherlands Heart Foundation. -
Risk stratffication From survival studies (and our own clinical experience) we concluded that some Marfan patients develop aortic complications, that are not limited to the ascending aorta irrespective of known risk factors. Decreased aortic elasticity was considered as an additional functional risk factor for aortic dissection. Firstly, we determined breaking stress of the normal aorta and showed that aortic breaking stress was correlated with aortic elastic properties in vitro. Then we assessed elastic properties throughout the aorta by MRI in Marfan patients with a normal-sized aorta distal to the aortic root and matched controls. It was shown that Marfan patients already exhibit reduced aortic elasticity in these undilated aortic tracts. In another study it was shown that treatment with [Bblocking agents increased aortic elasticity in Marfan patients.
New Insights In the electrical treat-nent of atrial flbrillation: the atrial defibrillator
Future perspectives
Follow-up of the Marfan patients who underwent MRI for detection of reduced elasticity will be performed. In due course, the value of aortic elasticity on aortic complications and mortality in Marfan patients will become clear. Aortic elasticity of Marfan patients who underwent prophylactic repair of the aortic root and the occurrence or proximal coronary dilation in these patients are still to be investigated. Assessment of aortic root elasticity seems to require a complicated three-dimensional approach, for which MRI, continuously measured blood pressure (non-invasively by Finapress), and finite element reconstruction are necessary. Moreover, the value of dural ectasia as a sign for Marfan syndrome in 60
Doctoral candidate: Dr. C. Timmermans, Promotors: Prof. Dr. H.J.J. Wellens, Co-promotor: Dr. L-M. Rodriguez
Antiarrhythmic drugs and external cardioversion are the primary modes of treatment of patients with atrial fibrillation. Because of the limited efficacy and safety of antiarrhythmic drugs and repeated hospitalisations for external cardioversion, requiring general anaesthesia, several nonpharmacological options have been developed, especially for patients with recurrent atrial fibrillation. One of them, the implantable atrial defibrillator, has only recently been introduced. In the thesis, the first experience with the atrial defibrillator is described. The atrial defibrillator is a pectorally implanted device connected to right atrial and coronary sinus defibrillation leads and a bipolar ventricular pacing lead (figure 1). Biphasic shocks are programmable up to 6 J. The device uses a dual algorithm to detect atrial fibrillation and delivers R-wave synchronous defibrillation shocks to convert atrial fibrillation to sinus rhythm. It is also able to pace the ventricle in case ofpostshock bradycardia. The device can be programmed in an automatic mode with periodic activation of the device for AF detection and defibrillation. The patient-activated mode allows the patient to activate the device with a magnet. In a prospective, worldwide, multicentre study, the device was implanted in patients without structural heart disease and was able to
Figure 1. Chest x-ray showing the atrial defibrillator connected with a right atrium defibrillation lead, a coronary sinus defibrillation lead, and a right ventricular bipolar lead.
restore sinus rhythm promptly and safely with low amounts of energy. In these patients, the frequency of long-lasting atrial fibrillation episodes, which were treated under physician observation, decreased. However, the number and duration ofshort-lasting, nontreated episodes did not change during a 20-month study period. Ambulatory therapy with the atrial defibrillator is feasible as the device can terminate most episodes of atrial fibrillation in the patient's ambient setting without induction of ventricular proarrhythmia. Interestingly, in the majority of the patients, atrial fibrillation can be treated with the device without sedation. The need for sedation is related to the number of shocks delivered to treat an atrial fibrillation episode. Although some shocks initially fail to convert atrial fibrinlation to sinus rhythm, reinitiation of atrial fibrillation within minutes after a successful cardioversion (IRAF) is the most frequent cause of the delivery of additional shocks. Because atrial fibrillation mainly occurs in patients with structural heart disease, the feasibility of the atrial defibrillator was also evaluated in a patient with congenital heart disease. The device proved to be a valid treatment option in this patient crippled by the arrhythmia. Netherlands Heart Joumal, Volume 9, Number 1, April 2001
University news
Whether an implantable atrial defibrillator improves quality of life and is cost-effective needs to be studied. U
Strategles of coronary reperfusion In acute myocardial infarction for patients admitted to hospitals without angloplasty facilities
Doctoral candidate: Dr. A.J.M. Oude Ophuis, Promotors: Prof. Dr. F.W.H.M. Bar, Prof. Dr. H.J.J. Wellens, Co-promotor: Dr. F. Vermeer
At present, two reperfusion techniques have proven their efficacy in the treatment of acute myocardial infarction; administration of a fibrinolytic agent and mechanical reopening of the occluded vessel followed by percutaneous transluminal coronary angioplasty (PTCA). Rescue PTCA after failed thrombolysis is likely to be beneficial, but definite proof is not available. So far, angioplasty in acute myocardial infarction has primarily been studied and practised in patients who were admitted directly to a PTCA centre. However, the majority of patients with an acute myocardial infarction present to hospitals without PTCA facilities (85% of the patients in the Netherlands). The purpose of this thesis is to compare three strategies of management of extensive acute myocardial infarction; a) thrombolytic therapy, b) thrombolytic therapy followed by acute coronary angiography and (if indicated) Table 2. Where to go from here; prehospital triage?
Netherlands Heart Joumal, Volume 9, Number 1, Aprl 2001
Table 1. LIMI study: Clinical course during one year follow-up. Thrombolysis Thrombolysis + rescue PTCA N N Number of patients 75 74 Deceased 6 (5) 7 (6) Thrombolic stroke 1 (1) 2 (1) Haemorrhagic stroke 1 (1) 2 (2) Recurrent infarction 9 (7) 5 (4) Late PTCA/CABG 29 (23) 24 (17) Recurrent 10 (6) 9 (5) ischaemia only* None of the above 33 (48) 38 (44)
Prlmary PTCA N 75 9 2 0 4 10 10
(5) (2) (0) (1) (6) (6)
47 (58)
Data are of one year follow-up. Between brackets data conceming 42 days follow-up. *Recurrent ischaemia without infarction and not followed by intervention (PTCA/CABG).
PTCA, and c) primary PTCA, in patients who are admitted to a hospital without angioplasty facilities. The questions to be answered in this thesis were threefold. The first important clinical question was whether the angiographic and clinical outcome differs between rescue and primary PTCA?P Secondly, can noninvasive parameters of reperfusion be of help in selecting patients for acute coronary angiography and subsequent coronary angioplasty? Thirdly, do patients who are admitted to a centre without PTCA facilities benefit from early transfer to a PTCA centre for rescue
rescue angioplasty or primary angio-
plasty and can this be performedwith a favourable relation between cost and effect? Conclusions
1. The clinical and angiographic outcome for patients with acute myocardial infarction with angiographically proven inadequate coronary flow is similar for early rescue PTCA and primary PTCA. 2. Reperfusion parameters are of help in identifying patients with acute myocardial infarction with open coronary arteries in which subsequent angioplasty is not necessary. TIMI 3 flow cannot reliably be discriminated from TIMI 2 flow. However, the prognosis of patients with acute
myocardial infarction with positive criteria of reperfusion is excellent. 3. Acute transfer of patients with extensive acute myocardial infarction from a hospital without angioplasty facilities to a
hospital with angioplasty facilities is safe and at least in the Maastricht setting feasible and can be done in a therapeutically acceptable time window. Transferring patients to a PTCA centre may improve clinical outcome but at significant cost (table 1). The extra cost per additional MACE free survivor in comparison with thrombolytic treatment seems most favourable for primary PTCA. The treatment with 'thrombolysis only' remains the best alternative in an environment of limited resources. Where to go from here? (table 2) For slideshow: www.doctoroudeophuis.com
61
