Ignite Creation Date:
2024-05-05 @ 12:02 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00223704
Status:
COMPLETED
Last Update Posted:
2013-11-25
First Post:
2005-09-19
Brief Title:
Bradykinin Receptor Antagonism During Cardiopulmonary Bypass
Sponsor:
Vanderbilt University
Organization:
Vanderbilt University
Study Overview
Official Title:
Bradykinin Receptor Antagonism During Cardiopulmonary Bypass
Status:
COMPLETED
Status Verified Date:
2013-10
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:
BRAC
Brief Summary:
Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary bypass CPB CPB is associated with significant morbidity including the transfusion of allogenic blood products inflammation and hemodynamic instability In fact approximately 20 of all blood products transfused are associated with coronary artery bypass grafting procedures Transfusion of allogenic blood products is associated with well-documented morbidity and increased mortality after cardiac surgery Enhanced fibrinolysis contributes to increased blood product transfusion in the perioperative period The current proposal tests the central hypothesis that endogenous bradykinin contributes to the hemodynamic fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will reduce hypotension inflammation and transfusion requirements In SPECIFIC AIM 1 we will test the hypothesis that the fibrinolytic and inflammatory response to CPB differ during ACE inhibition and angiotensin II type 1 receptor antagonism In SPECIFIC AIM 2 we will test the hypothesis that bradykinin B2 receptor antagonism attenuates the hemodynamic fibrinolytic and inflammatory response to CPB In SPECIFIC AIM 3 we will test the hypothesis that bradykinin B2 receptor antagonism reduces the risk of allogenic blood product transfusion in patients undergoing CPB These studies promise to provide important information regarding the effects of drugs that interrupt the RAS and generate new strategies to reduce morbidity in patients undergoing CPB
Detailed Description:
Morbidity of cardiopulmonary bypass Each year more than a million patients worldwide undergo cardiac surgery Nearly all cardiac surgeries are performed on unbeating hearts supported by CPB Although the use of off-pump coronary artery bypass surgery procedures are increasing concerns regarding incomplete revascularization and reduced venous graft patency limit the use of this technique to specific patients CPB activates various humoral cascades including the coagulation cascade the KKS the fibrinolytic cascade and causes a systemic inflammatory response syndrome Activation of these systems can lead to hypotension fever disseminated intravascular coagulation diffuse tissue edema or in extreme cases to multiple organ failure Activation of the KKS contributes to the hemodynamic perturbations fibrinolysis and inflammatory response observed in patients undergoing CPB Aprotinin a non-specific serine protease inhibitor that works in part by decreasing bradykinin generation decreases fibrinolysis hypotension and the systemic inflammatory response associated with CPB Aprotinin decreases blood loss and transfusion requirements however its use is mainly limited to redo-cardiac surgery because of cost Other factors that may limit the widespread use of aprotinin include an increased risk for renal dysfunction allergic reaction and non-specificity of the drug Bradykinin mediates most of the effects of the KKS Thus bradykinin receptor antagonism has the potential to modulate the effects of KKS activation during CPB The purpose of this proposal is to test the hypothesis that endogenous bradykinin contributes to the hemodynamic fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will reduce hypotension inflammation and transfusion requirements The proposed studies promise to lead to novel therapies to reduce morbidity associated with CPB
Cardiopulmonary bypass activates the kallikrein-kinin system KKS Several groups including ours have reported that bradykinin concentrations increase during CPB For example Campbell et al demonstrated that bradykinin levels increase 10 to 20-fold during the first 10 minutes of CPB returned to basal levels by 70 minutes of CPB and remained 17 to 52-fold elevated after CPB Plasma and tissue kallikrein were reduced by 80 and 60 respectively during the first minute of CPB Similarly we have demonstrated that bradykinin increases significantly during CPB and that ACE inhibition and smoking potentiate the kinin response during CPB
Fibrinolytic response to cardiopulmonary bypass CPB increases t-PA antigen and activity in a time-dependent manner The fibrinolytic response during CPB is heterogeneous with t-PA levels varying as much as 250-fold The mechanism of t-PA release during CPB is likely multifactorial As outlined above we and others have shown that CPB increases bradykinin a potent stimulus to t-PA release In addition thrombin or complement generated during CPB may stimulate the release of t-PA from endothelium In addition to the changes in t-PA concentrations during CPB PAI-1 activity falls because of hemodilution and the rise in t-PA release which consumes active PAI-1 Plasmin generation increases over 100-fold while D-dimer generation increases 200-fold within 5 minutes of CPB initiation For the remainder of the CPB average plasmin and D-dimer levels remain 20-fold to 30-fold above baseline levels The postoperative period is marked by a systemic inflammatory response caused by a combination of CPB and surgery producing an acute -phase response that results in increased PAI-1 production PAI-1 levels begin to rise about 2 hours after surgery Once CPB is over PAI-1 levels continue to rise and peak during the first 12-36 hours postoperatively and return to normal by the second postoperative day Thus the fibrinolytic response to CPB is characterized by an initial hyperfibrinolytic phase that begins with a rapid rise in t-PA plasmin and D-dimer concentrations followed by a postoperative hypofibrinolytic phase associated with a rise in PAI-1 secretion and a fall in t-PA concentrations
Interaction between the renin-angiotensin system RAS the KKS and fibrinolytic system There is evidence that fibrinolytic balance is regulated by the RAS and the KKS ACE is strategically poised to control fibrinolytic balance by promoting the breakdown of bradykinin and the conversion of Ang I to Ang II Ang II causes the release of PAI-1 thus inhibiting fibrinolysis Bradykinin stimulates t-PA release through its B2 receptor ACE inhibition decreases PAI-1 antigen levels and increases endothelial t-PA release through endogenous bradykinin In addition ACE inhibition enhances exogenous bradykinin-mediated vasodilation and t-PA release The augmentation of bradykinin-induced vasodilation the increase in t-PA and the decrease in PAI-1 described with ACE inhibition in patients with ischemic heart disease may contribute to the primary mechanism of the anti-ischemic effects associated with chronic ACE inhibitor therapy We have demonstrated that inpatients undergoing coronary artery bypass grafting CABG requiring CPB not only did ACE inhibition increase fibrinolytic activity by decreasing PAI-1 antigen and increasing t-PA activity but also enhanced the kinin response Increased PAI-1 concentrations in the perioperative period are associated with acute vein graft thrombosis Thus ACE inhibitors have a potential to reduce the risk of acute graft thrombosis through their effects on Ang II generation by attenuating the PAI-1 response after CABG As opposed to the beneficial effects of ACE inhibition on PAI-1 the augmentation of the kinin response during CPB may have detrimental effects including increased fibrinolysis with consequent bleeding and hypotension The effect of angiotensin II type 1 AT1 receptor antagonist on the fibrinolytic response to CPB is not known Inpatients with essential hypertension AT1 receptor antagonist decreases PAI-1 antigen in some but not other studies In Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and AT1 receptor antagonist modulate the fibrinolytic and inflammatory response to CPB differently
Bradykinin receptor antagonism could reduce the hypotensive response to CPB Low systemic vascular resistance SVR commonly occurs during and early after CPB It is usually transient and easy to treat Occasionally patients have a more severe and persistent fall in SVR referred to postoperative vasodilatory shock Risk factors for vasodilatory shock includes the preoperative use of ACE inhibitors low left ventricular ejection fraction and heart failure syndrome Treatment is frequently required to maintain adequate perfusion pressure during CPB and to establish satisfactory hemodynamics when ready to separate the patient from bypass This usually entails counteracting the effect of the vasodilatory mediators by administration of drugs such as norepinephrine or phenylephrine Although usually effective and safe these drugs can redistribute blood flow in such a way as to compromise the splanchnic and renal circulation Several mediators are thought to be responsible for producing postoperative shock including bradykinin For example there is an inverse correlation between bradykinin concentrations and mean arterial pressure during CPB suggesting that bradykinin is an important mediator in the decrease in SVR We and others have shown that bradykinin induces vasodilation through its B2 receptor In contract B1 receptor stimulation does not cause vasodilation As outlined under PRELIMINARY STUDIES we have demonstrated that endogenous bradykinin contributes to protamine-related hypotension following CPB and that bradykinin receptor antagonism administered just prior to protamine attenuates this hypotensive response In Specific Aim 2 we will test the hypothesis that bradykinin receptor antagonism modulate the hemodynamic changes observed during CPB
Bradykinin receptor antagonism could reduce hyperfibrinolysis and CPB-associated blood loss Inhibiting hyperfibrinolysis during CPB reduces blood loss and blood product requirements On the other hand modulating the hypofibrinolytic phase after CPB has the potential to reduce thrombotic complications We and others have shown that bradykinin stimulates t-PA release from human forearm vasculature and the coronary circulation through a NO synthase-independent and cyclooxygenase-independent pathway As with vasodilation bradykinin-stimulated t-PA release is mediated via the B2 receptor Several groups have reported that bradykinin concentrations increase during CPB We demonstrated a direct correlation between bradykinin and t-PA concentrations during CPB suggesting that bradykinin plays an important role in activating the fibrinolytic response during CPB As outlined under PRELIMINARY STUDIES we have shown that HOE 140 a B2 receptor antagonist administered prior to CPB blunts the increase in D-dimer similar to e-aminocaproic acid Thus B2 receptor antagonism has the potential to reduce bradykinin-mediated fibrinolysis during CPB In Specific Aim 2 we will test the hypothesis that bradykinin receptor antagonism modulate the fibrinolytic response observed during CPB
Bradykinin receptor antagonism could reduce the inflammatory response to CPB During CPB exposure of blood to bioincompatible surfaces of the extracorporeal circuit as well as tissue ischemia and reperfusion associated with the procedure induce the activation of several major humoral pathways of inflammation Bradykinin produces many of the characteristics of the inflammatory state such as changes in local blood pressure edema and pain resulting in vasodilation and increased microvessel permeability Bradykinin activates NF-kB and upregulates interleukinIL-1b and TNFa-stimulated IL-8 production through the B2 receptor In addition bradykinin stimulates the release of IL-6 from a variety of cells The growing knowledge of the biological role of kinins in particular in inflammation has fueled the development of potent and selective kinin receptor antagonist as potential therapeutics For example the bradykinin antagonist deltibant CP-0127 showed a significant improvement in the 28-day risk-adjusted survival of patients with gram-negative sepsis In an animal model of intestinal ischemia-reperfusion injury B2 receptor antagonism inhibited reperfusion induced increases in vascular permeability neutrophil recruitment and expression of B1 receptor mRNA The role of B2 receptor antagonist in myocardial ischemia-reperfusion injury is more controversial Kumari et al demonstrated a protective effect of HOE 140 during in vivo ischemia-reperfusion injury whereas in isolated rabbit heart studies CP-0127 impaired recovery from acute coronary ischemia This contradictory results may be the result of different antagonist used differences in species sensitivity or different experimental protocols The role of B1 receptor antagonist in inflammation is unclear In contrast to the constitutively expressed bradykinin B2 receptor bradykinin B1 receptor expression is upregulated following an inflammatory insult or ischemia-reperfusion injury It appears that each kinin receptor subtype mediates different aspects of the inflammatory response However B1 receptor antagonism administered prior to CPB may be detrimental For example Siebeck et al demonstrated that B2 receptor blockade attenuates endotoxin-induced mortality in pigs whereas additional B1 receptor blockade seemed to reverse these beneficial effects Taken together B2 receptor antagonism may decrease the acute inflammatory response whereas additional B1 receptor blockade may be harmful These studies and also the fact that aprotinin exerts part of its beneficial effects through a reduction in bradykinin concentrations suggest the hypothesis that pharmacological strategies to block the bradykinin B2 receptor may be superior to reducing bradykinin concentrations in modulating the inflammatory response to CPB
The RAS KKS and inflammation Activation of the RAS exerts proinflammatory effects For example Ang II activates the transcription factor nuclear factor NF-kB which in turn regulates genes involved in cellular recruitment and the inflammatory cytokine cascade Ang II induces the synthesis and secretion of the inflammatory interleukin IL-6 As mentioned above bradykinin produces many of the characteristics of the inflammatory state and upregulates IL-1b and TNFa-stimulated IL-8 and stimulates the release of IL-6 Thus both Ang II and bradykinin stimulates the release of IL-6 ACE inhibitor treatment is associated with a reduction in IL-6 response to CPB In a randomized non-blinded study Trevelyan and colleagues20 demonstrated that ACE inhibition produced a highly significant decrease of 51 in the release of IL-6 in patients identified as high producers of IL-6 by the -174 GC polymorphism whereas losartan had a similar but less marked effect Potential mechanisms for this variation in IL-6 response between ACE inhibitors and angiotensin receptor blocker may be due to their differential effect on Ang II formation and bradykinin degradation Furthermore bradykinin-induced increases in IL-6 protein and total mRNA are inhibited by the selective B2 receptor antagonist HOE-140 but not by a selective B1 receptor antagonist In Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and angiotensin II type 1 AT1 receptor antagonist modulate the fibrinolytic and inflammatory response to CPB differently
Cardiopulmonary bypass activates the kallikrein-kinin system KKS Several groups including ours have reported that bradykinin concentrations increase during CPB For example Campbell et al demonstrated that bradykinin levels increase 10 to 20-fold during the first 10 minutes of CPB returned to basal levels by 70 minutes of CPB and remained 17 to 52-fold elevated after CPB Plasma and tissue kallikrein were reduced by 80 and 60 respectively during the first minute of CPB Similarly we have demonstrated that bradykinin increases significantly during CPB and that ACE inhibition and smoking potentiate the kinin response during CPB
Fibrinolytic response to cardiopulmonary bypass CPB increases t-PA antigen and activity in a time-dependent manner The fibrinolytic response during CPB is heterogeneous with t-PA levels varying as much as 250-fold The mechanism of t-PA release during CPB is likely multifactorial As outlined above we and others have shown that CPB increases bradykinin a potent stimulus to t-PA release In addition thrombin or complement generated during CPB may stimulate the release of t-PA from endothelium In addition to the changes in t-PA concentrations during CPB PAI-1 activity falls because of hemodilution and the rise in t-PA release which consumes active PAI-1 Plasmin generation increases over 100-fold while D-dimer generation increases 200-fold within 5 minutes of CPB initiation For the remainder of the CPB average plasmin and D-dimer levels remain 20-fold to 30-fold above baseline levels The postoperative period is marked by a systemic inflammatory response caused by a combination of CPB and surgery producing an acute -phase response that results in increased PAI-1 production PAI-1 levels begin to rise about 2 hours after surgery Once CPB is over PAI-1 levels continue to rise and peak during the first 12-36 hours postoperatively and return to normal by the second postoperative day Thus the fibrinolytic response to CPB is characterized by an initial hyperfibrinolytic phase that begins with a rapid rise in t-PA plasmin and D-dimer concentrations followed by a postoperative hypofibrinolytic phase associated with a rise in PAI-1 secretion and a fall in t-PA concentrations
Interaction between the renin-angiotensin system RAS the KKS and fibrinolytic system There is evidence that fibrinolytic balance is regulated by the RAS and the KKS ACE is strategically poised to control fibrinolytic balance by promoting the breakdown of bradykinin and the conversion of Ang I to Ang II Ang II causes the release of PAI-1 thus inhibiting fibrinolysis Bradykinin stimulates t-PA release through its B2 receptor ACE inhibition decreases PAI-1 antigen levels and increases endothelial t-PA release through endogenous bradykinin In addition ACE inhibition enhances exogenous bradykinin-mediated vasodilation and t-PA release The augmentation of bradykinin-induced vasodilation the increase in t-PA and the decrease in PAI-1 described with ACE inhibition in patients with ischemic heart disease may contribute to the primary mechanism of the anti-ischemic effects associated with chronic ACE inhibitor therapy We have demonstrated that inpatients undergoing coronary artery bypass grafting CABG requiring CPB not only did ACE inhibition increase fibrinolytic activity by decreasing PAI-1 antigen and increasing t-PA activity but also enhanced the kinin response Increased PAI-1 concentrations in the perioperative period are associated with acute vein graft thrombosis Thus ACE inhibitors have a potential to reduce the risk of acute graft thrombosis through their effects on Ang II generation by attenuating the PAI-1 response after CABG As opposed to the beneficial effects of ACE inhibition on PAI-1 the augmentation of the kinin response during CPB may have detrimental effects including increased fibrinolysis with consequent bleeding and hypotension The effect of angiotensin II type 1 AT1 receptor antagonist on the fibrinolytic response to CPB is not known Inpatients with essential hypertension AT1 receptor antagonist decreases PAI-1 antigen in some but not other studies In Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and AT1 receptor antagonist modulate the fibrinolytic and inflammatory response to CPB differently
Bradykinin receptor antagonism could reduce the hypotensive response to CPB Low systemic vascular resistance SVR commonly occurs during and early after CPB It is usually transient and easy to treat Occasionally patients have a more severe and persistent fall in SVR referred to postoperative vasodilatory shock Risk factors for vasodilatory shock includes the preoperative use of ACE inhibitors low left ventricular ejection fraction and heart failure syndrome Treatment is frequently required to maintain adequate perfusion pressure during CPB and to establish satisfactory hemodynamics when ready to separate the patient from bypass This usually entails counteracting the effect of the vasodilatory mediators by administration of drugs such as norepinephrine or phenylephrine Although usually effective and safe these drugs can redistribute blood flow in such a way as to compromise the splanchnic and renal circulation Several mediators are thought to be responsible for producing postoperative shock including bradykinin For example there is an inverse correlation between bradykinin concentrations and mean arterial pressure during CPB suggesting that bradykinin is an important mediator in the decrease in SVR We and others have shown that bradykinin induces vasodilation through its B2 receptor In contract B1 receptor stimulation does not cause vasodilation As outlined under PRELIMINARY STUDIES we have demonstrated that endogenous bradykinin contributes to protamine-related hypotension following CPB and that bradykinin receptor antagonism administered just prior to protamine attenuates this hypotensive response In Specific Aim 2 we will test the hypothesis that bradykinin receptor antagonism modulate the hemodynamic changes observed during CPB
Bradykinin receptor antagonism could reduce hyperfibrinolysis and CPB-associated blood loss Inhibiting hyperfibrinolysis during CPB reduces blood loss and blood product requirements On the other hand modulating the hypofibrinolytic phase after CPB has the potential to reduce thrombotic complications We and others have shown that bradykinin stimulates t-PA release from human forearm vasculature and the coronary circulation through a NO synthase-independent and cyclooxygenase-independent pathway As with vasodilation bradykinin-stimulated t-PA release is mediated via the B2 receptor Several groups have reported that bradykinin concentrations increase during CPB We demonstrated a direct correlation between bradykinin and t-PA concentrations during CPB suggesting that bradykinin plays an important role in activating the fibrinolytic response during CPB As outlined under PRELIMINARY STUDIES we have shown that HOE 140 a B2 receptor antagonist administered prior to CPB blunts the increase in D-dimer similar to e-aminocaproic acid Thus B2 receptor antagonism has the potential to reduce bradykinin-mediated fibrinolysis during CPB In Specific Aim 2 we will test the hypothesis that bradykinin receptor antagonism modulate the fibrinolytic response observed during CPB
Bradykinin receptor antagonism could reduce the inflammatory response to CPB During CPB exposure of blood to bioincompatible surfaces of the extracorporeal circuit as well as tissue ischemia and reperfusion associated with the procedure induce the activation of several major humoral pathways of inflammation Bradykinin produces many of the characteristics of the inflammatory state such as changes in local blood pressure edema and pain resulting in vasodilation and increased microvessel permeability Bradykinin activates NF-kB and upregulates interleukinIL-1b and TNFa-stimulated IL-8 production through the B2 receptor In addition bradykinin stimulates the release of IL-6 from a variety of cells The growing knowledge of the biological role of kinins in particular in inflammation has fueled the development of potent and selective kinin receptor antagonist as potential therapeutics For example the bradykinin antagonist deltibant CP-0127 showed a significant improvement in the 28-day risk-adjusted survival of patients with gram-negative sepsis In an animal model of intestinal ischemia-reperfusion injury B2 receptor antagonism inhibited reperfusion induced increases in vascular permeability neutrophil recruitment and expression of B1 receptor mRNA The role of B2 receptor antagonist in myocardial ischemia-reperfusion injury is more controversial Kumari et al demonstrated a protective effect of HOE 140 during in vivo ischemia-reperfusion injury whereas in isolated rabbit heart studies CP-0127 impaired recovery from acute coronary ischemia This contradictory results may be the result of different antagonist used differences in species sensitivity or different experimental protocols The role of B1 receptor antagonist in inflammation is unclear In contrast to the constitutively expressed bradykinin B2 receptor bradykinin B1 receptor expression is upregulated following an inflammatory insult or ischemia-reperfusion injury It appears that each kinin receptor subtype mediates different aspects of the inflammatory response However B1 receptor antagonism administered prior to CPB may be detrimental For example Siebeck et al demonstrated that B2 receptor blockade attenuates endotoxin-induced mortality in pigs whereas additional B1 receptor blockade seemed to reverse these beneficial effects Taken together B2 receptor antagonism may decrease the acute inflammatory response whereas additional B1 receptor blockade may be harmful These studies and also the fact that aprotinin exerts part of its beneficial effects through a reduction in bradykinin concentrations suggest the hypothesis that pharmacological strategies to block the bradykinin B2 receptor may be superior to reducing bradykinin concentrations in modulating the inflammatory response to CPB
The RAS KKS and inflammation Activation of the RAS exerts proinflammatory effects For example Ang II activates the transcription factor nuclear factor NF-kB which in turn regulates genes involved in cellular recruitment and the inflammatory cytokine cascade Ang II induces the synthesis and secretion of the inflammatory interleukin IL-6 As mentioned above bradykinin produces many of the characteristics of the inflammatory state and upregulates IL-1b and TNFa-stimulated IL-8 and stimulates the release of IL-6 Thus both Ang II and bradykinin stimulates the release of IL-6 ACE inhibitor treatment is associated with a reduction in IL-6 response to CPB In a randomized non-blinded study Trevelyan and colleagues20 demonstrated that ACE inhibition produced a highly significant decrease of 51 in the release of IL-6 in patients identified as high producers of IL-6 by the -174 GC polymorphism whereas losartan had a similar but less marked effect Potential mechanisms for this variation in IL-6 response between ACE inhibitors and angiotensin receptor blocker may be due to their differential effect on Ang II formation and bradykinin degradation Furthermore bradykinin-induced increases in IL-6 protein and total mRNA are inhibited by the selective B2 receptor antagonist HOE-140 but not by a selective B1 receptor antagonist In Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and angiotensin II type 1 AT1 receptor antagonist modulate the fibrinolytic and inflammatory response to CPB differently
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?:
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Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| HL085740-02 | None | None | None |