UNIVERSITY NEWS
Einthoven
Dissertatie
Cardiologle
Prijzen 2001
For the thirteenth year in a row, the Netherlands Society ofCardiology (NVVC), the Interuniversity Cardiology Institute ofthe Netherlands, and the sponsor, Sanofi Synthelabo, are supporting the competition for the best three PhD theses published last year on a cardiovascular subject. The prizes carry the name of one of the great men in the history of Cardiology: Willem Einthoven (1860-1927), the pioneer of the human ECG. The jury, consisting ofrepresentatives ofthe NVVC, the ICIN, and Sanofi Synthelabo, were offered 15 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 26 April 2002. The winner of the first, second and third prize will be chosen by the audience. Summaries of the three nominated PhD theses are given below.
Prof:dr. H.J.J. Wellens, chairman of the Jury. Oral anticoagulant therapy In percutaneous coronary Intervention
Percutaneous coronary intervention (PCI) is still complicated by thrombotic events. This is probably due to incomplete platelet activation and incomplete reduction of thrombin formation by the routinely used combination of aspirin and heparin. The main subject of this thesis is the prospective randomised Balloon Angioplasty and Anticoagulation Study (BAAS). The BAAS was the first trial to study the effect of oral anticoagulant treatment started before PCI and continued for six months. This trial randomly assigned 530 patients to aspirin plus counarins and 528 patients to aspirin alone. Target INRwas 2.1-4.8. Halfofthe patients were randomised to angiographic follow-up. At one year, the composite endpoint of death, myocardial infarction, target-lesion revascularisation and stroke was observed in 14.3% of the patients treated with aspirin plus coumarins as compared with 20.3% of the patients treated with aspirin alone (RR, 0.71; 95% CI, 0.54-0.93). The incidence of major bleeding and false aneurysm during hospitalisation was 3.2% and 1.0%, respectively. The benefit ofcoumarmns was observed in both stented (34%) and non-stented patients. In addition it was demonstrated that patients with an optimal level of anticoagulation,
218
Survival fire from AMI, reintervention or stroke
'86% 86%
*
1
2
3
4
5
6
7
8
9
1 -11 12
months defined as an INRin the target range for at least 70% ofthe follow-up time, suffered both significantly less thrombotic events at one year (RR, 0.33; 95% CI, 0.19-0.57) and had a significantly larger minimal luminal diameter of the treated artery at six months as compared with patients with a suboptimal level of anticoagulation. The effect ofcoumanns on events may not be the only one to take into consideration. Costs may be important too. Coumarins may save costs due to a reduction in events, but it needs to be realised that treatment with coumarins requires regular monitoring, and that there will be additional costs associated with the increased risk ofbleedings. Therefore,
in BAAS, costs and effects of coumarin treatment were analysed based on the occurrence of both cardiac and bleeding events. When including all costs the savings associated with coumarin treatment were estimated at e 235 after one year. This was in particular due to less reinterventions in the coumarin group.
Platelet activation plays a major role in acute vessel closure after PCI. In BAAS, the effect of pretreatment with coumarins on the platelet activation state was analysed by wholeblood flow cytometry with epitopedependent monodonal antibodies. It was shown that coumarins reduced the number ofactivated platelets both before and after PCI, which is in
Netherlands Heart Joumal, Volume 10, Number 4, April 2002
UNIVERSITY NEWS
agreement with its clinical effect of reducing procedural complications. In addition, it was hypothesised that the routinely used dose of aspirin is too low to prevent platelet activation during PCI. Therefore, the effect of an additional high-dose bolus of 1000 mg aspirin on top of daily 100 aspirin on platelet activation before and after PCI was studied. Additional high-dose aspirin significantly reduced the platelet activation state before and after intervention, which could mean that a high-dose bolus aspirin may reduce early thrombotic complications in patients undergoing PCI. In condusion, BAAS shows that the antithrombotic treatment of patients undergoing PCI can be improved with the use ofthe inexpensive drugs coumarin and aspirin. -
J.M. ten Berg.
equivocal left main coronary artery disease FFRwas valuable in deciding between bypass surgery or conservative therapy. Other diagnostic applications are identification of (the) culprit lesion(s) in case of multivessel disease, to indicate the exact location of a lesion in case of overprojection or other situations where the angiographic image is ambiguous. Furthermore, FFR can also be used before hospital discharge after myocardial infarction to demonstrate viability and to determine whether a residual stenosis needs to be deleted. Finally, the most powerfiul use of this technique is constituted by retrieving the pressure wire under fluoroscopy from a distal coronary position to a proximal position at hyperaemia (socalled pressure pull-back recording, see figure 1). In this way segmental information on the distribution of focal (single or sequential) or diffise disease along the complete coronary artery is obtained. Such detailed
spatial information is not obtainable by any other invasive or non-invasive method. FFR can also be applied during coronary intervention to quantify improvement in coronary blood flow after angioplasty. Both after regular balloon angioplasty and after coronary stenting, a strong inverse relation was demonstrated between increase in FFRand restenosis rate in a follow-up of up to two years. Finally, by measuring coronary wedge pressure during balloon occlusion, FFRcan be used to quantify maximum collateral blood flow in relation to normal maximum blood flow (fractional collateral flow reserve). It has been shown that this index of collateral blood flow, calculated in this way, is inversely related to the chance of an adverse cardiac event in up to two years of follow-up. In conclusion FFR provides unique physiological information, can
Coronary pressure measurement and ftactional flow reserve for decision making In the catheterlsation laboratory Over the past decade fractional flow reserve (FFR) has emerged as a reliable tool for assessment ofcoronary artery disease. FFR is determined from coronary pressure measurement during cardiac catheterisation and is defined as maximum myocardial blood flow in the presence of a coronary stenosis divided by normal maximum flow. It quantifies to what extent maximum coronary blood flow is decreased by the presence of the stenosis. In contrast to other inP_.WpihdbmwoAD le_d __Abfuw _mb vasive indexes, such as coronary flow reserve, FFR is not dependent on changes in blood pressure, contractility and heart rate. The normal value of this index is 1.0 and the threshold value of 0.75 discriminates stenoses that are associated with ischaemia from those that are not. Recently it was demonstrated in the prospective randomised DEFER study that revascularisation of a stenosis is most appropriate ifFFRis below 0.75, whereas it was safe to Figure 1. Example ofpressure pull-back recording along a coronary artery. During defer PTCAwhen FFRexceeds 0.75. hyperaemia, underfluoroscopy, the pressure wire is retrievedfrom a distal to a proximal In another study, it was demonstrated position along the coronary artery. When the pressure sensor crosses either of the stenoses, that in patients with angiographically changes in pressure are registered (arrows on tracings) confirmingfocal disease. Netherlands Heart Journal, Volume 10, Number 4, April 2002
219
UNIVERSITY NEWS
be easily applied in both diagnostic and interventional procedures, and improves outcome in patients with coronary artery disease. -
A
B
Jan Willem Bech. Mechanism of delayed lschaemiaInduced ventricular arrhythmias Sudden death in the setting ofacute myocardial ischaemia accounts for approximately 12,000 deaths in the Netherlands each year. Lethal ventricular arrhythmias, in particular ventricular fibrillation (VF), occur in two distinct phases during the acute phase of myocardial ischaemia that are separated by an arrhythmia-free interval. Except for the association between arrhythmias and the onset of cellular uncoupling, little information is available on the mechanism of the second, lB phase. Cellular uncoupling refers to the closure of gap junctions between cardiomyocytes, resulting in increased intercellular resistance and subsequent conduction slowing and block, factors that predispose for reentrant arrhythmias. We hypothesise that intrinsically viable tissues during acute myocardial ischaemia (i.e. the ischaemic subepicardium and subendocardium) are electrically depressed through persisting residual coupling with irreversibly damaged tissue (i.e. the ischaemic midmyocardium). The electrophysiological changes in the subepicardium caused by this electrotonic depression form an arrhythmogenic substrate. The implications are: 1. The subepicardial and subendocardial layer are viable after ischaemia. 2. Arrhythmias are associated with a moderate decrease of cellular coupling, and
progression of cellular uncoupling results in termination ofthe arrhythmogenic substrate. 3. Microscopic heterogeneities are absent because the entire subepicardium becomes electrically depressed. 4. VF activation patterns become restricted to the two-dimensional plane of the ischaemic subepicardium (that survives ischaemia). We found that 69% of the ischaemic subepicardium was viable 220
IIss Is3 Iso
O 1020 30 40 5060 7080 90100 Tissue impedance rise (%)
.iOm
.~~~~x
m
Figure 1. A. Unipolar electrograms recordedfrom an electrode in the ischaemic zone duringattempts to induce VF. No arrhythmias occur with three premature stimuli before ischaemia. At 17, 26 and 32 minutes of ischaemia, VF was provoked with a decreasing number ofpremature stimuli (arrows). Thereafter, the number of triqgers to induce VF increases after39 and 50 minutes. Arrows denote stimulus artefacts. The stimulusprotocol is displayed at the bottom ofthefigure. B. VF inducibility related to relative increase in tissue impedance. VF was induced in nine out of ten experiments, tissue impedance increased up to 40%. Asterisk indicates p
Einthoven
Dissertatie
Cardiologle
Prijzen 2001
For the thirteenth year in a row, the Netherlands Society ofCardiology (NVVC), the Interuniversity Cardiology Institute ofthe Netherlands, and the sponsor, Sanofi Synthelabo, are supporting the competition for the best three PhD theses published last year on a cardiovascular subject. The prizes carry the name of one of the great men in the history of Cardiology: Willem Einthoven (1860-1927), the pioneer of the human ECG. The jury, consisting ofrepresentatives ofthe NVVC, the ICIN, and Sanofi Synthelabo, were offered 15 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 26 April 2002. The winner of the first, second and third prize will be chosen by the audience. Summaries of the three nominated PhD theses are given below.
Prof:dr. H.J.J. Wellens, chairman of the Jury. Oral anticoagulant therapy In percutaneous coronary Intervention
Percutaneous coronary intervention (PCI) is still complicated by thrombotic events. This is probably due to incomplete platelet activation and incomplete reduction of thrombin formation by the routinely used combination of aspirin and heparin. The main subject of this thesis is the prospective randomised Balloon Angioplasty and Anticoagulation Study (BAAS). The BAAS was the first trial to study the effect of oral anticoagulant treatment started before PCI and continued for six months. This trial randomly assigned 530 patients to aspirin plus counarins and 528 patients to aspirin alone. Target INRwas 2.1-4.8. Halfofthe patients were randomised to angiographic follow-up. At one year, the composite endpoint of death, myocardial infarction, target-lesion revascularisation and stroke was observed in 14.3% of the patients treated with aspirin plus coumarins as compared with 20.3% of the patients treated with aspirin alone (RR, 0.71; 95% CI, 0.54-0.93). The incidence of major bleeding and false aneurysm during hospitalisation was 3.2% and 1.0%, respectively. The benefit ofcoumarmns was observed in both stented (34%) and non-stented patients. In addition it was demonstrated that patients with an optimal level of anticoagulation,
218
Survival fire from AMI, reintervention or stroke
'86% 86%
*
1
2
3
4
5
6
7
8
9
1 -11 12
months defined as an INRin the target range for at least 70% ofthe follow-up time, suffered both significantly less thrombotic events at one year (RR, 0.33; 95% CI, 0.19-0.57) and had a significantly larger minimal luminal diameter of the treated artery at six months as compared with patients with a suboptimal level of anticoagulation. The effect ofcoumanns on events may not be the only one to take into consideration. Costs may be important too. Coumarins may save costs due to a reduction in events, but it needs to be realised that treatment with coumarins requires regular monitoring, and that there will be additional costs associated with the increased risk ofbleedings. Therefore,
in BAAS, costs and effects of coumarin treatment were analysed based on the occurrence of both cardiac and bleeding events. When including all costs the savings associated with coumarin treatment were estimated at e 235 after one year. This was in particular due to less reinterventions in the coumarin group.
Platelet activation plays a major role in acute vessel closure after PCI. In BAAS, the effect of pretreatment with coumarins on the platelet activation state was analysed by wholeblood flow cytometry with epitopedependent monodonal antibodies. It was shown that coumarins reduced the number ofactivated platelets both before and after PCI, which is in
Netherlands Heart Joumal, Volume 10, Number 4, April 2002
UNIVERSITY NEWS
agreement with its clinical effect of reducing procedural complications. In addition, it was hypothesised that the routinely used dose of aspirin is too low to prevent platelet activation during PCI. Therefore, the effect of an additional high-dose bolus of 1000 mg aspirin on top of daily 100 aspirin on platelet activation before and after PCI was studied. Additional high-dose aspirin significantly reduced the platelet activation state before and after intervention, which could mean that a high-dose bolus aspirin may reduce early thrombotic complications in patients undergoing PCI. In condusion, BAAS shows that the antithrombotic treatment of patients undergoing PCI can be improved with the use ofthe inexpensive drugs coumarin and aspirin. -
J.M. ten Berg.
equivocal left main coronary artery disease FFRwas valuable in deciding between bypass surgery or conservative therapy. Other diagnostic applications are identification of (the) culprit lesion(s) in case of multivessel disease, to indicate the exact location of a lesion in case of overprojection or other situations where the angiographic image is ambiguous. Furthermore, FFR can also be used before hospital discharge after myocardial infarction to demonstrate viability and to determine whether a residual stenosis needs to be deleted. Finally, the most powerfiul use of this technique is constituted by retrieving the pressure wire under fluoroscopy from a distal coronary position to a proximal position at hyperaemia (socalled pressure pull-back recording, see figure 1). In this way segmental information on the distribution of focal (single or sequential) or diffise disease along the complete coronary artery is obtained. Such detailed
spatial information is not obtainable by any other invasive or non-invasive method. FFR can also be applied during coronary intervention to quantify improvement in coronary blood flow after angioplasty. Both after regular balloon angioplasty and after coronary stenting, a strong inverse relation was demonstrated between increase in FFRand restenosis rate in a follow-up of up to two years. Finally, by measuring coronary wedge pressure during balloon occlusion, FFRcan be used to quantify maximum collateral blood flow in relation to normal maximum blood flow (fractional collateral flow reserve). It has been shown that this index of collateral blood flow, calculated in this way, is inversely related to the chance of an adverse cardiac event in up to two years of follow-up. In conclusion FFR provides unique physiological information, can
Coronary pressure measurement and ftactional flow reserve for decision making In the catheterlsation laboratory Over the past decade fractional flow reserve (FFR) has emerged as a reliable tool for assessment ofcoronary artery disease. FFR is determined from coronary pressure measurement during cardiac catheterisation and is defined as maximum myocardial blood flow in the presence of a coronary stenosis divided by normal maximum flow. It quantifies to what extent maximum coronary blood flow is decreased by the presence of the stenosis. In contrast to other inP_.WpihdbmwoAD le_d __Abfuw _mb vasive indexes, such as coronary flow reserve, FFR is not dependent on changes in blood pressure, contractility and heart rate. The normal value of this index is 1.0 and the threshold value of 0.75 discriminates stenoses that are associated with ischaemia from those that are not. Recently it was demonstrated in the prospective randomised DEFER study that revascularisation of a stenosis is most appropriate ifFFRis below 0.75, whereas it was safe to Figure 1. Example ofpressure pull-back recording along a coronary artery. During defer PTCAwhen FFRexceeds 0.75. hyperaemia, underfluoroscopy, the pressure wire is retrievedfrom a distal to a proximal In another study, it was demonstrated position along the coronary artery. When the pressure sensor crosses either of the stenoses, that in patients with angiographically changes in pressure are registered (arrows on tracings) confirmingfocal disease. Netherlands Heart Journal, Volume 10, Number 4, April 2002
219
UNIVERSITY NEWS
be easily applied in both diagnostic and interventional procedures, and improves outcome in patients with coronary artery disease. -
A
B
Jan Willem Bech. Mechanism of delayed lschaemiaInduced ventricular arrhythmias Sudden death in the setting ofacute myocardial ischaemia accounts for approximately 12,000 deaths in the Netherlands each year. Lethal ventricular arrhythmias, in particular ventricular fibrillation (VF), occur in two distinct phases during the acute phase of myocardial ischaemia that are separated by an arrhythmia-free interval. Except for the association between arrhythmias and the onset of cellular uncoupling, little information is available on the mechanism of the second, lB phase. Cellular uncoupling refers to the closure of gap junctions between cardiomyocytes, resulting in increased intercellular resistance and subsequent conduction slowing and block, factors that predispose for reentrant arrhythmias. We hypothesise that intrinsically viable tissues during acute myocardial ischaemia (i.e. the ischaemic subepicardium and subendocardium) are electrically depressed through persisting residual coupling with irreversibly damaged tissue (i.e. the ischaemic midmyocardium). The electrophysiological changes in the subepicardium caused by this electrotonic depression form an arrhythmogenic substrate. The implications are: 1. The subepicardial and subendocardial layer are viable after ischaemia. 2. Arrhythmias are associated with a moderate decrease of cellular coupling, and
progression of cellular uncoupling results in termination ofthe arrhythmogenic substrate. 3. Microscopic heterogeneities are absent because the entire subepicardium becomes electrically depressed. 4. VF activation patterns become restricted to the two-dimensional plane of the ischaemic subepicardium (that survives ischaemia). We found that 69% of the ischaemic subepicardium was viable 220
IIss Is3 Iso
O 1020 30 40 5060 7080 90100 Tissue impedance rise (%)
.iOm
.~~~~x
m
Figure 1. A. Unipolar electrograms recordedfrom an electrode in the ischaemic zone duringattempts to induce VF. No arrhythmias occur with three premature stimuli before ischaemia. At 17, 26 and 32 minutes of ischaemia, VF was provoked with a decreasing number ofpremature stimuli (arrows). Thereafter, the number of triqgers to induce VF increases after39 and 50 minutes. Arrows denote stimulus artefacts. The stimulusprotocol is displayed at the bottom ofthefigure. B. VF inducibility related to relative increase in tissue impedance. VF was induced in nine out of ten experiments, tissue impedance increased up to 40%. Asterisk indicates p
