Ignite Creation Date:
2024-05-06 @ 12:38 AM
Last Modification Date:
2024-10-26 @ 10:53 AM
Study NCT ID:
NCT01625832
Status:
COMPLETED
Last Update Posted:
2012-06-21
First Post:
2012-06-15
Brief Title:
Effects of Coronary Sinus Occlusion on Myocardial Ischemia Pilot Study
Sponsor:
Insel Gruppe AG University Hospital Bern
Organization:
Insel Gruppe AG University Hospital Bern
Study Overview
Official Title:
Effects of Coronary Sinus Occlusion on Myocardial Ischemia Pilot Study
Status:
COMPLETED
Status Verified Date:
2012-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Coronary artery disease CAD is the leading cause of morbidity and mortality in industrialized countries despite advances in medical interventional and surgical revascularization therapies In both acute myocardial infarction AMI and chronic stable disease standard therapeutic approaches may fail to restore tissue perfusion Indeed a substantial number of chronic CAD patients may not be amenable to standard revascularization therapies or percutaneous coronary intervention PCI may fail to restore coronary artery patency following an acute vessel occlusion no-reflow phenomenon microvascular obstruction As a consequence the long pursued strategy of augmenting myocardial perfusion by diverting blood from the coronary venous system to an ischemic region venous retroperfusion has again gained attention during recent years Occlusion of the coronary sinus CSO was introduced to provide retroperfusion by transient augmentation of coronary venous pressure Different devices using CSO have been invented and evaluated in animal models and small clinical trials eg intermittent CSO ICSO and pressure-controlled intermittent CSO PICSO which seem to be effective for myocardial salvage However they are not yet employed in clinical routine and importantly the exact underlying mechanisms by which retroperfusion due to CSO may reduce myocardial ischemia are not yet understood
As natural bypasses coronary collaterals are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries that represent an alternative source of blood supply to a myocardial area jeopardized by ischemia Collaterals of the heart can be assessed quantitatively by coronary pressure measurements which have become the gold standard collateral flow index CFIPoccl-CVPPao-CVP Theoretically augmentation of coronary sinus pressure by CSO with an increase of venous backflow reaches the upstream collateral circulation which in turn could lead to improved collateral flow from non-ischemic areas to an occluded ischemic myocardial region by upstream flow diversion On the other hand when considering the formula to calculate pressure-derived CFI it seems that augmentation of coronary back pressure would rather impair collateral flow since central venous pressure is coronary sinus pressure However the regional effect of a global increase in coronary sinus pressure is unlikely to be as uniform as the above formula implies ie the response is more pronounced in some than in other vascular territories In experimental studies using dogs with abundant collaterals elevation of coronary sinus pressure caused an augmentation of regional myocardial blood flow in the collateralized area In contrast when ICSO was performed in pigs which possess no preformed collaterals it increased the pressure distal of an occluded LAD but did not improve blood flow or left ventricular function
In conclusion experimental studies and pathophysiologic considerations suggest a necessary role of the collateral circulation for the beneficial effects of coronary sinus occlusion CSO observed in animals and humans however no clinical data are available so far on the effect of CSO on myocardial ischemia in the presence of varying collateral flow
Study hypotheses
1 CSO decreases intra-coronary ECG ST-segment elevation during a 2-minute coronary occlusion
2 The decrease in occlusive intra-coronary ECG ST elevation during CSO is directly proportional to CFI
3 Coronary sinus oxygen saturation during coronary occlusion with CSO is directly proportional to CFI
As natural bypasses coronary collaterals are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries that represent an alternative source of blood supply to a myocardial area jeopardized by ischemia Collaterals of the heart can be assessed quantitatively by coronary pressure measurements which have become the gold standard collateral flow index CFIPoccl-CVPPao-CVP Theoretically augmentation of coronary sinus pressure by CSO with an increase of venous backflow reaches the upstream collateral circulation which in turn could lead to improved collateral flow from non-ischemic areas to an occluded ischemic myocardial region by upstream flow diversion On the other hand when considering the formula to calculate pressure-derived CFI it seems that augmentation of coronary back pressure would rather impair collateral flow since central venous pressure is coronary sinus pressure However the regional effect of a global increase in coronary sinus pressure is unlikely to be as uniform as the above formula implies ie the response is more pronounced in some than in other vascular territories In experimental studies using dogs with abundant collaterals elevation of coronary sinus pressure caused an augmentation of regional myocardial blood flow in the collateralized area In contrast when ICSO was performed in pigs which possess no preformed collaterals it increased the pressure distal of an occluded LAD but did not improve blood flow or left ventricular function
In conclusion experimental studies and pathophysiologic considerations suggest a necessary role of the collateral circulation for the beneficial effects of coronary sinus occlusion CSO observed in animals and humans however no clinical data are available so far on the effect of CSO on myocardial ischemia in the presence of varying collateral flow
Study hypotheses
1 CSO decreases intra-coronary ECG ST-segment elevation during a 2-minute coronary occlusion
2 The decrease in occlusive intra-coronary ECG ST elevation during CSO is directly proportional to CFI
3 Coronary sinus oxygen saturation during coronary occlusion with CSO is directly proportional to CFI
Detailed Description:
Background
The concept of venous retroperfusion in coronary artery disease Coronary artery disease CAD is the leading cause of morbidity and mortality in industrialized countries despite advances in medical interventional and surgical revascularization therapies The different strategies aiming at restoration of coronary blood flow and subsequent improvement of myocardial perfusion have led to increased survival rates of CAD patients with both acute myocardial infarction AMI and chronic stable disease However in both situations standard therapeutic approaches may fail to restore tissue perfusion First up to 20 of patients with chronic CAD may not be amenable to standard revascularization therapies and may suffer from refractory angina pectoris andor chronic heart failure Second despite the high success rates of percutaneous coronary intervention PCI in restoration of coronary artery patency following an acute vessel occlusion AMI blood flow of the infarct related artery is often still markedly impaired TIMI2 no-reflow phenomenon microvascular obstruction As a consequence the long pursued strategy of augmenting myocardial perfusion by diverting blood from the coronary venous system to an ischemic region venous retroperfusion has again gained attention during recent years Already in 1898 the experimental work of Pratt suggested that venous retroperfusion may provide nutritional delivery to the myocardium In the mid 20ieth century the concept was followed by cardiac surgeons who introduced the coronary venous bypass graft for myocardial revascularization CVBG which was soon replaced by its arterial counterpart CABG and also used this protection technique during valve surgery More than 25 years ago occlusion of the coronary sinus CSO was introduced to provide retroperfusion by transient augmentation of coronary venous pressure Since then different devices using CSO have been invented and evaluated in animal models and small clinical trials eg intermittent CSO ICSO and pressure-controlled intermittent CSO PICSO Miracor Medical Systems Austria as well as a coronary sinus reducer stent Neovasc Medical Israel At least the systems using PICSO seem to be effective for myocardial salvage however they are not yet employed in clinical routine possibly due to their difficult usage and potential risks sinus damage thrombosis stenosis chronic myocardial edema Importantly the exact underlying mechanisms by which retroperfusion due to CSO may reduce myocardial ischemia are not yet understood It has been proposed that aside from augmented delivery of blood to the ischemic region the following mechanisms may play a role a functional venous microcirculation less blockade of the microcirculation washout of reactive oxygen species ROS diminished granulocyte trapping and improvement of cellularinterstitial edema Importantly it is very likely that the extent of coronary collaterals play a crucial role for the efficacy of PICSO However only a limited number of experimental studies have addressed this issue so far
Coronary collateral circulation As natural bypasses coronary collaterals are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries that represent an alternative source of blood supply to a myocardial area jeopardized by ischemia In patients with CAD a well-developed coronary collateral circulation contributes to reduction of infarct size LV-dysfunction and mortality Collaterals of the heart can be assessed quantitatively by coronary flow velocity or pressure measurements which have become the gold standard The theoretical basis of this method relates to the fact that perfusion pressure minus the central venous back pressure or flow velocity signals obtained distal to an occluded stenosis originate from collaterals The measurement of aortic and coronary pressure or flow velocity provides the basis for the calculation of a pressure- or velocity-derived collateral flow index CFI both of which express the amount of flow via collaterals to the vascular region of interest as a fraction of the flow via the normally patent vessel CFI measurements have been documented to be accurate with regard to ECG derived dichotomous collateral assessment with regard to each other but also to quantitative myocardial perfusion imaging by contrast echocardiography during balloon occlusion Pressure- and Doppler-derived coronary collateral measurements are regarded as the reference method for quantitative clinical assessment of coronary collateral flow Pressure- and Doppler-derived coronary collateral measurements are regarded as the reference method for quantitative clinical assessment of coronary collateral flow
As a consequence it can be imagined that at the origin of preformed collateral channels in the non-ischemic area blood is diverged away from the downstream microcirculation due to regionally augmented back pressure At the orifice of the preformed collaterals perfusion pressure as well as back pressure are low resulting in a low driving pressure ie the necessary condition to receive blood from the collateral-supplying region limited by increased wall stress respectively by an extravascular tissue pressure above approximately 27 mmHg
These theoretical considerations have been investigated only experimentally so far Sato et al performed regional myocardial blood flow measurements in dogs after ligation of the left anterior descending coronary artery LAD with or without coronary sinus pressure elevation to 30 mmHg In this study regional myocardial blood flow in the collateralized area was augmented by an elevation of coronary sinus pressure however this effect was present only in the periphery of the ischemic region Using a very similar model namely LAD occlusion in dogs and sinus pressure augmentation above 30 mmHg by CSO Ido et al showed that CSO augments subendocardial but not subepicardial myocardial blood flow in the ischemic region ie collateral flow Interestingly CSO also normalized the subepicardial blood flow in the non-ischemic region which was increased by the LAD occlusion Moreover after maximal vasodilation with adenosine these effects were abolished and blood flow with CSO was decreased in the ischemic region indicating collateral steal17 In addition to these studies Toggart et al demonstrated years earlier in a pig model that ICSO augmentation above 60 mmHg increased the pressure distal of an occluded LAD but did not improve blood flow or left ventricular function Since pigs do not have preformed collaterals this study importantly indicates a crucial role of collateral flow for the therapeutic efficacy of ICSO Of note the results of this study also argue against the proposed washout hypothesis In conclusion experimental studies and pathophysiologic considerations suggest a necessary role of the collateral circulation for the beneficial effects of coronary sinus occlusion observed in animals and humans however no clinical data are available so far on the effect of CSO on myocardial ischemia in the presence of varying collateral flow
Objective
The purpose of this study in patients with chronic stable CAD undergoing elective coronary angiography is to determine the effect of CSO on the level of myocardial ischemia during a brief coronary occlusion and the influence of the collateral circulation on this effect
Methods
Study protocol
Diagnostic coronary angiography and LV angiography
Administration of 5000 units of heparin iv and 2 puffs of oral isosorbide-dinitrate
Study inclusion if there is one stenotic lesion eligible for PCI
Randomization for CSO first or no CSO first protocol
Insertion of a 6 French Swan-Ganz balloon-tipped catheter into the coronary sinus
Preparation for PCI of the coronary stenosis responsible for the patients symptoms
Installation of intra-coronary ECG via PCI guidewire
PCI using a pressure sensor-tipped angioplasty guidewire
CSO protocol
2-minute coronary artery balloon occlusion with intra-coronary ECG with CSO
CSO 2-minute coronary sinus balloon occlusion
Collection of blood from the coronary sinus
10-minute interval after the first balloon occlusion no CSO protocol
2-minute coronary artery balloon occlusion with intra-coronary ECG without CSO
no coronary sinus occlusion
Collection of blood from the coronary sinus
The concept of venous retroperfusion in coronary artery disease Coronary artery disease CAD is the leading cause of morbidity and mortality in industrialized countries despite advances in medical interventional and surgical revascularization therapies The different strategies aiming at restoration of coronary blood flow and subsequent improvement of myocardial perfusion have led to increased survival rates of CAD patients with both acute myocardial infarction AMI and chronic stable disease However in both situations standard therapeutic approaches may fail to restore tissue perfusion First up to 20 of patients with chronic CAD may not be amenable to standard revascularization therapies and may suffer from refractory angina pectoris andor chronic heart failure Second despite the high success rates of percutaneous coronary intervention PCI in restoration of coronary artery patency following an acute vessel occlusion AMI blood flow of the infarct related artery is often still markedly impaired TIMI2 no-reflow phenomenon microvascular obstruction As a consequence the long pursued strategy of augmenting myocardial perfusion by diverting blood from the coronary venous system to an ischemic region venous retroperfusion has again gained attention during recent years Already in 1898 the experimental work of Pratt suggested that venous retroperfusion may provide nutritional delivery to the myocardium In the mid 20ieth century the concept was followed by cardiac surgeons who introduced the coronary venous bypass graft for myocardial revascularization CVBG which was soon replaced by its arterial counterpart CABG and also used this protection technique during valve surgery More than 25 years ago occlusion of the coronary sinus CSO was introduced to provide retroperfusion by transient augmentation of coronary venous pressure Since then different devices using CSO have been invented and evaluated in animal models and small clinical trials eg intermittent CSO ICSO and pressure-controlled intermittent CSO PICSO Miracor Medical Systems Austria as well as a coronary sinus reducer stent Neovasc Medical Israel At least the systems using PICSO seem to be effective for myocardial salvage however they are not yet employed in clinical routine possibly due to their difficult usage and potential risks sinus damage thrombosis stenosis chronic myocardial edema Importantly the exact underlying mechanisms by which retroperfusion due to CSO may reduce myocardial ischemia are not yet understood It has been proposed that aside from augmented delivery of blood to the ischemic region the following mechanisms may play a role a functional venous microcirculation less blockade of the microcirculation washout of reactive oxygen species ROS diminished granulocyte trapping and improvement of cellularinterstitial edema Importantly it is very likely that the extent of coronary collaterals play a crucial role for the efficacy of PICSO However only a limited number of experimental studies have addressed this issue so far
Coronary collateral circulation As natural bypasses coronary collaterals are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries that represent an alternative source of blood supply to a myocardial area jeopardized by ischemia In patients with CAD a well-developed coronary collateral circulation contributes to reduction of infarct size LV-dysfunction and mortality Collaterals of the heart can be assessed quantitatively by coronary flow velocity or pressure measurements which have become the gold standard The theoretical basis of this method relates to the fact that perfusion pressure minus the central venous back pressure or flow velocity signals obtained distal to an occluded stenosis originate from collaterals The measurement of aortic and coronary pressure or flow velocity provides the basis for the calculation of a pressure- or velocity-derived collateral flow index CFI both of which express the amount of flow via collaterals to the vascular region of interest as a fraction of the flow via the normally patent vessel CFI measurements have been documented to be accurate with regard to ECG derived dichotomous collateral assessment with regard to each other but also to quantitative myocardial perfusion imaging by contrast echocardiography during balloon occlusion Pressure- and Doppler-derived coronary collateral measurements are regarded as the reference method for quantitative clinical assessment of coronary collateral flow Pressure- and Doppler-derived coronary collateral measurements are regarded as the reference method for quantitative clinical assessment of coronary collateral flow
As a consequence it can be imagined that at the origin of preformed collateral channels in the non-ischemic area blood is diverged away from the downstream microcirculation due to regionally augmented back pressure At the orifice of the preformed collaterals perfusion pressure as well as back pressure are low resulting in a low driving pressure ie the necessary condition to receive blood from the collateral-supplying region limited by increased wall stress respectively by an extravascular tissue pressure above approximately 27 mmHg
These theoretical considerations have been investigated only experimentally so far Sato et al performed regional myocardial blood flow measurements in dogs after ligation of the left anterior descending coronary artery LAD with or without coronary sinus pressure elevation to 30 mmHg In this study regional myocardial blood flow in the collateralized area was augmented by an elevation of coronary sinus pressure however this effect was present only in the periphery of the ischemic region Using a very similar model namely LAD occlusion in dogs and sinus pressure augmentation above 30 mmHg by CSO Ido et al showed that CSO augments subendocardial but not subepicardial myocardial blood flow in the ischemic region ie collateral flow Interestingly CSO also normalized the subepicardial blood flow in the non-ischemic region which was increased by the LAD occlusion Moreover after maximal vasodilation with adenosine these effects were abolished and blood flow with CSO was decreased in the ischemic region indicating collateral steal17 In addition to these studies Toggart et al demonstrated years earlier in a pig model that ICSO augmentation above 60 mmHg increased the pressure distal of an occluded LAD but did not improve blood flow or left ventricular function Since pigs do not have preformed collaterals this study importantly indicates a crucial role of collateral flow for the therapeutic efficacy of ICSO Of note the results of this study also argue against the proposed washout hypothesis In conclusion experimental studies and pathophysiologic considerations suggest a necessary role of the collateral circulation for the beneficial effects of coronary sinus occlusion observed in animals and humans however no clinical data are available so far on the effect of CSO on myocardial ischemia in the presence of varying collateral flow
Objective
The purpose of this study in patients with chronic stable CAD undergoing elective coronary angiography is to determine the effect of CSO on the level of myocardial ischemia during a brief coronary occlusion and the influence of the collateral circulation on this effect
Methods
Study protocol
Diagnostic coronary angiography and LV angiography
Administration of 5000 units of heparin iv and 2 puffs of oral isosorbide-dinitrate
Study inclusion if there is one stenotic lesion eligible for PCI
Randomization for CSO first or no CSO first protocol
Insertion of a 6 French Swan-Ganz balloon-tipped catheter into the coronary sinus
Preparation for PCI of the coronary stenosis responsible for the patients symptoms
Installation of intra-coronary ECG via PCI guidewire
PCI using a pressure sensor-tipped angioplasty guidewire
CSO protocol
2-minute coronary artery balloon occlusion with intra-coronary ECG with CSO
CSO 2-minute coronary sinus balloon occlusion
Collection of blood from the coronary sinus
10-minute interval after the first balloon occlusion no CSO protocol
2-minute coronary artery balloon occlusion with intra-coronary ECG without CSO
no coronary sinus occlusion
Collection of blood from the coronary sinus
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None