Myocardial Reperfusion Injury
Conditions
Keywords
Coronary Atherosclerosis, Microvascular Dysfunction, Non-ST Elevation Myocardial Infarction
Brief summary
Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor and its expression is increased in atherosclerotic coronary arteries. Our hypothesis is that increased activity of the endogenous endothelin system contributes to microvascular dysfunction, and adjunctive therapy with an endothelin receptor antagonist will result in improved microvascular blood flow. Aims: The aims of the study are to assess in patients with non ST-elevation myocardial infarction, whether: 1) PCI causes an increase in coronary blood ET-1 level; 2) an endothelin receptor antagonist acutely improves coronary microvascular blood flow following PCI. Non-ST segment elevation myocardial infarction (NSTEMI) is one type of heart attack. It is defined as the development of heart muscle necrosis results from an acute interruption of blood supply to a part of the heart which is demonstrated by an elevation of cardiac markers Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) in the blood and the absence of ST-segment elevation in ECG (electrocardiography). ST-segment is a portion of ECG, its elevation indicates full thickness damage of heart muscle. Absence of ST-segment elevation in NSTEMI indicates partial thickness damage of heart muscle occurs. Therefore, NSTEMI is less severe type of heart attack compared to STEMI (ST-segment elevation myocardial infarction) in which full thickness damage of heart muscle occurs.
Detailed description
Our hypothesis is that the endogenous endothelin system contributes to microvascular dysfunction and impaired myocardial reperfusion following successful PCI for non ST-elevation MI, and that endothelin receptor antagonism will improve microvascular flow. The study will provide new insight into the humoral regulation of the microcirculation in patients presenting with acute coronary syndromes. General methods: This section describes our approach to investigating the specific aims. The study is a prospective, double blind, placebo-controlled trial to assess the efficacy of a selective endothelin type A receptor antagonist (BQ-123), as adjunctive therapy for PCI for non ST elevation MI. The control group will receive placebo rather than another vasodilator in order to specifically elucidate the role of the endogenous endothelin system.
Interventions
DRUGBQ-123
BQ-123 is a cyclic peptide consisting of five amino acids. BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).
DRUGPlacebo
Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Clinical diagnosis of unstable angina or non ST-elevation myocardial infarction, and requiring clinically indicated PCI for the management of non ST elevation acute coronary syndrome.
Exclusion criteria
* Systemic hypotension (systolic \<90 mmHg) * Heart failure or known ejection fraction \< 30% * Left main disease * Culprit lesion is in a saphenous vein graft * 100% occlusion of the culprit vessel or culprit is an ostial right coronary stenosis * Currently enrolled in other active cardiovascular investigational studies * Severe endocrine, hepatic, or renal disorders * Pregnancy or lactation * Federal Medical Center inmates * Inability or unwillingness to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) | immediately following PCI procedure | Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | immediately pre-PCI, 8 hours post-PCI, 16 hours post-PCI | CK-MB is a cardiac marker that can demonstrate the development of heart muscle necrosis resulting from an acute interruption of blood supply to a part of the heart. CK-MB is measured by a blood test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BQ-123 BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). | 11 |
| Placebo Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unsuccessful PCI | 1 | 0 |
Baseline characteristics
| Characteristic | BQ-123 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 11.2 | 64 years STANDARD_DEVIATION 12.5 | 64.27 years STANDARD_DEVIATION 11.6 |
| Region of Enrollment United States | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 |
Outcome results
Primary
Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI)
Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography.
Time frame: immediately following PCI procedure
Population: One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BQ-123 | Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) | 30 cm/s |
| Placebo | Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) | 19 cm/s |
p-value: 0.029t-test, 2 sided
Secondary
Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI
CK-MB is a cardiac marker that can demonstrate the development of heart muscle necrosis resulting from an acute interruption of blood supply to a part of the heart. CK-MB is measured by a blood test.
Time frame: immediately pre-PCI, 8 hours post-PCI, 16 hours post-PCI
Population: One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BQ-123 | Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | % Change immediate pre-PCI, 8 hr post-PCI | -17 percent change |
| BQ-123 | Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | % Change immediate pre-PCI, 16 hr post-PCI | -17 percent change |
| Placebo | Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | % Change immediate pre-PCI, 8 hr post-PCI | 26 percent change |
| Placebo | Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | % Change immediate pre-PCI, 16 hr post-PCI | 107 percent change |
Comparison: Change between the groups from immediate pre-PCI and 8 hours post PCI.p-value: 0.019t-test, 2 sided
Comparison: Change between the groups from immediate pre-PCI and 16 hours post-PCI.p-value: 0.007t-test, 2 sided