Abstract
Background
In this prospective study, we compared the invasive measures of microvascular function in two subsets: patients with pharmacoinvasive thrombolysis for STEMI, and patients undergoing percutaneous coronary intervention (PCI) for NSTEMI.
Methods
The study consisted of 17 patients with STEMI referred for cardiac catheterisation post thrombolysis, and 20 patients with NSTEMI. Coronary physiological indexes were measured in each patient before and after PCI.
Results
The median pre-PCI index of microcirculatory function (IMR) at baseline was significantly higher in the STEMI group than the NSTEMI group (26 units vs. 15 units, p = 0.02). Following PCI, IMR decreased in both groups (STEMI 20 units vs. NSTEMI 14 units, p = 0.10). There was an inverse correlation between post PCI IMR and left ventricular ejection fraction (LVEF) ( r = −0.52, p = 0.001). Furthermore, post PCI IMR was an independent predictor of index admission LVEF in the total population ( β = −0.388, p = 0.02).
Conclusion
Invasive measures of microvascular function are inferior in a pharmacoinvasive STEMI group compared to a clinically stable NSTEMI group. In the STEMI population, the IMR following coronary intervention appears to predict LVEF.
Highlights
- •
There is an increasing importance attributed to the function of the microcirculation in improving outcomes ACS.
- •
Coronary physiological indexes were measured before and after PCI, in 17 patients with STEMI post thrombolysis and 20 patients with NSTEMI.
- •
Invasive measures of microvascular function (IMR, CFR & RRR) are impaired in a pharmacoinvasive STEMI population compared to a NSTEMI population.
- •
In this select STEMI population, IMR following coronary intervention was the only significant predictor of LVEF during the index admission.
1
Introduction
There is an increasing importance attributed to the function of the microcirculation in improving outcomes in acute coronary syndrome (ACS). The index of microcirculatory resistance (IMR) is a readily available, reproducible and quantitative, coronary wire-based technique for invasively assessing microvascular function that is independent of the epicardial circulation [ , ]. The evidence for the clinical utility of IMR is increasing with post procedure IMR having been shown to predict left ventricular recovery at three to six months and long term clinical outcomes and prognosis [ ].
The assessment of microvascular function with IMR has not been adequately addressed in patients with STEMI undergoing a pharmacoinvasive strategy and the NSTEMI population. This is particularly relevant in Australia, where the ‘tyranny of distance’ impedes the ability to deliver primary percutaneous coronary intervention (PCI) for STEMI in patients who do not have early access to a PCI capable centre for urgent revascularisation. In this prospective study, we assessed and compared the invasive measures of microvascular function in these subsets of ACS patients.
2
Methods
2.1
Patients
The study population consisted of 17 patients with STEMI referred to St Vincent’s Hospital, Melbourne, for cardiac catheterisation within 48 h of thrombolysis and 20 patients with clinically stable NSTEMI. Patients were enrolled if ≥18 years old and written informed consent was obtained. STEMI patients were enrolled if they were clinically stable post thrombolysis from a referral centre, defined as pain free with a resolution of ST elevation. Those patients with ongoing pain and ST elevation despite thrombolysis were not enrolled and managed with rescue PCI. Patients were excluded if they were in cardiogenic shock, had an anaemia of unknown aetiology, previous myocardial infarction in the culprit artery, previous coronary artery bypass surgery, significant valvular heart disease, chronic atrial fibrillation, severe renal impairment (eGFR <30 mls/min), active inflammatory or malignancy or those with a contraindication to adenosine. Angiographic exclusions included left main coronary artery with a stenosis >50%, chronic total occlusions and patients with angiographically normal coronary arteries. The Human Research Ethics Committee at St Vincent’s Hospital, Melbourne, approved the study protocol.
2.2
Study protocol
All patients received a weight based dose of unfractionated heparin at the discretion of the operator, to maintain an activated clotting time of >250 s. All patients were prescribed aspirin and clopidogrel before catheterisation. A 6 F coronary guiding catheter was used to engage the culprit coronary artery and all patients received 200 μg of intracoronary nitroglycerin in the culprit vessel. A 0.014 in. coronary temperature and pressure sensing guide wire (St. Jude Medical, Inc.; St. Paul, Minn) was calibrated and then equalized to the guiding catheter pressure with the distal sensor placed at the ostium of the coronary artery. The wire was then passed beyond the stenosis to the distal third of the vessel.
2.3
Physiological assessment
Coronary physiological indexes (IMR, coronary flow reserve, fractional flow reserve, collateral flow index and resistive reserve ratio) were measured in each patient before and after PCI. Microvascular function was measured using IMR as previously described [ ]. In brief, 3 ml of normal saline at room temperature was injected intracoronary to produce three reproducible and consistent thermodilution curves and transit times. The average of these three transit times was taken as the mean baseline transit time ( Tmn Base ) and shown previously to be inversely proportional to coronary blood flow [ ]. Intravenous adenosine was then administered via the right femoral or an antecubital vein (140 μg/kg/min) to achieve maximal hyperaemia. Following this, a further three thermodilution curves and transit times were produced and averaged to obtain the mean hyperaemic transit time ( Tmn Hyp ). A physiological response to adenosine was observed in all patients.
The index of microcirculatory resistance was then calculated using the Eq. (1) IMR = Pd Hyp × Tmn Hyp or incorporating the coronary wedge pressure in the presence of a severe stenosis [ ]: IMR c = Pa Hyp × Tmn Hyp ( Pd Hyp − Pw ) / ( Pa Hyp − Pw ), where Pd is the mean hyperaemic distal pressure, Tmn Hyp the mean hyperaemic transit time, Pa the mean hyperaemic aortic pressure and Pw the coronary wedge pressure. Coronary wedge pressure is defined as the distal coronary pressure obtained during a 30-second balloon inflation sufficient to occlude the culprit vessel and represents recruitable collateral vessels [ ].
Coronary flow reserve (CFR) was calculated by dividing the mean baseline transit time by the hyperaemic transit time. Fractional flow reserve (FFR) was defined as the mean distal coronary pressure divided by the mean aortic pressure during hyperaemia. Care was taken to ensure that the distal sensor was in the same position between measurements to avoid errors in transit time acquisition.
Pressure derived collateral flow index (CFI) is the ratio of coronary wedge pressure (Pw) to aortic pressure (Pa) during a 30 s balloon inflation during PCI (CFI = Pw / Pa ). Baseline resistance index (BR) reflects resting tone in the coronary microcirculation and was calculated using the equation: BR = Pa Base × Tmn Base ( Pd Base − Pw ) / ( Pa Base − Pw ), where Pa Base was the resting aortic pressure, Tmn Base the mean transit time under resting conditions, Pd Base the mean resting distal pressure and Pw the coronary wedge pressure.
To measure the ability of the coronary microcirculation to undergo vasodilatation in response to a pharmacological hyperaemic stimulus (i.e., adenosine), the resistive reserve ratio (RRR) was calculated. The RRR is given by the following equation: RRR = BR / IMR .
2.4
Evaluation of left ventricular function
During the index admission, transthoracic echocardiography was performed within 24 h of PCI to document left ventricular function (LVEF). Echocardiographic images were obtained using a VIVID 7 or E9 echocardiograph (GE Medical Systems, Princeton, New Jersey). Two-dimensional ventricular volumes and LVEF were measured from the 4 and 2 chamber areas using the modified Simpson’s rule.
2.5
Statistical analysis
Data was analysed using SPSS (SPSS, Inc., Chicago, IL) statistical software package. Normality of data was assessed with the Kolmogorov–Smirnov statistic. Continuous variables are expressed as mean ± standard deviation. Non-normally distributed data are summarized as the median and interquartile range. Comparisons between continuous variables were performed using the Student t -test or Mann-Whitney U test as appropriate. Comparisons within groups were performed using the Student t -test or Wilcoxon signed rank test as appropriate. Categorical variables are reported as frequencies and percentages. Comparisons between categorical variables were evaluated using the Fisher exact test or the Pearson chi-square test as appropriate.
2
Methods
2.1
Patients
The study population consisted of 17 patients with STEMI referred to St Vincent’s Hospital, Melbourne, for cardiac catheterisation within 48 h of thrombolysis and 20 patients with clinically stable NSTEMI. Patients were enrolled if ≥18 years old and written informed consent was obtained. STEMI patients were enrolled if they were clinically stable post thrombolysis from a referral centre, defined as pain free with a resolution of ST elevation. Those patients with ongoing pain and ST elevation despite thrombolysis were not enrolled and managed with rescue PCI. Patients were excluded if they were in cardiogenic shock, had an anaemia of unknown aetiology, previous myocardial infarction in the culprit artery, previous coronary artery bypass surgery, significant valvular heart disease, chronic atrial fibrillation, severe renal impairment (eGFR <30 mls/min), active inflammatory or malignancy or those with a contraindication to adenosine. Angiographic exclusions included left main coronary artery with a stenosis >50%, chronic total occlusions and patients with angiographically normal coronary arteries. The Human Research Ethics Committee at St Vincent’s Hospital, Melbourne, approved the study protocol.
2.2
Study protocol
All patients received a weight based dose of unfractionated heparin at the discretion of the operator, to maintain an activated clotting time of >250 s. All patients were prescribed aspirin and clopidogrel before catheterisation. A 6 F coronary guiding catheter was used to engage the culprit coronary artery and all patients received 200 μg of intracoronary nitroglycerin in the culprit vessel. A 0.014 in. coronary temperature and pressure sensing guide wire (St. Jude Medical, Inc.; St. Paul, Minn) was calibrated and then equalized to the guiding catheter pressure with the distal sensor placed at the ostium of the coronary artery. The wire was then passed beyond the stenosis to the distal third of the vessel.
2.3
Physiological assessment
Coronary physiological indexes (IMR, coronary flow reserve, fractional flow reserve, collateral flow index and resistive reserve ratio) were measured in each patient before and after PCI. Microvascular function was measured using IMR as previously described [ ]. In brief, 3 ml of normal saline at room temperature was injected intracoronary to produce three reproducible and consistent thermodilution curves and transit times. The average of these three transit times was taken as the mean baseline transit time ( Tmn Base ) and shown previously to be inversely proportional to coronary blood flow [ ]. Intravenous adenosine was then administered via the right femoral or an antecubital vein (140 μg/kg/min) to achieve maximal hyperaemia. Following this, a further three thermodilution curves and transit times were produced and averaged to obtain the mean hyperaemic transit time ( Tmn Hyp ). A physiological response to adenosine was observed in all patients.
The index of microcirculatory resistance was then calculated using the Eq. (1) IMR = Pd Hyp × Tmn Hyp or incorporating the coronary wedge pressure in the presence of a severe stenosis [ ]: IMR c = Pa Hyp × Tmn Hyp ( Pd Hyp − Pw ) / ( Pa Hyp − Pw ), where Pd is the mean hyperaemic distal pressure, Tmn Hyp the mean hyperaemic transit time, Pa the mean hyperaemic aortic pressure and Pw the coronary wedge pressure. Coronary wedge pressure is defined as the distal coronary pressure obtained during a 30-second balloon inflation sufficient to occlude the culprit vessel and represents recruitable collateral vessels [ ].
Coronary flow reserve (CFR) was calculated by dividing the mean baseline transit time by the hyperaemic transit time. Fractional flow reserve (FFR) was defined as the mean distal coronary pressure divided by the mean aortic pressure during hyperaemia. Care was taken to ensure that the distal sensor was in the same position between measurements to avoid errors in transit time acquisition.
Pressure derived collateral flow index (CFI) is the ratio of coronary wedge pressure (Pw) to aortic pressure (Pa) during a 30 s balloon inflation during PCI (CFI = Pw / Pa ). Baseline resistance index (BR) reflects resting tone in the coronary microcirculation and was calculated using the equation: BR = Pa Base × Tmn Base ( Pd Base − Pw ) / ( Pa Base − Pw ), where Pa Base was the resting aortic pressure, Tmn Base the mean transit time under resting conditions, Pd Base the mean resting distal pressure and Pw the coronary wedge pressure.
To measure the ability of the coronary microcirculation to undergo vasodilatation in response to a pharmacological hyperaemic stimulus (i.e., adenosine), the resistive reserve ratio (RRR) was calculated. The RRR is given by the following equation: RRR = BR / IMR .
2.4
Evaluation of left ventricular function
During the index admission, transthoracic echocardiography was performed within 24 h of PCI to document left ventricular function (LVEF). Echocardiographic images were obtained using a VIVID 7 or E9 echocardiograph (GE Medical Systems, Princeton, New Jersey). Two-dimensional ventricular volumes and LVEF were measured from the 4 and 2 chamber areas using the modified Simpson’s rule.
2.5
Statistical analysis
Data was analysed using SPSS (SPSS, Inc., Chicago, IL) statistical software package. Normality of data was assessed with the Kolmogorov–Smirnov statistic. Continuous variables are expressed as mean ± standard deviation. Non-normally distributed data are summarized as the median and interquartile range. Comparisons between continuous variables were performed using the Student t -test or Mann-Whitney U test as appropriate. Comparisons within groups were performed using the Student t -test or Wilcoxon signed rank test as appropriate. Categorical variables are reported as frequencies and percentages. Comparisons between categorical variables were evaluated using the Fisher exact test or the Pearson chi-square test as appropriate.
3
Results
3.1
Patient population
A total of 37 patients were assessed in this study; 17 presenting with STEMI undergoing a pharmacoinvasive strategy and 20 presenting with NSTEMI. Baseline clinical and procedural characteristics are presented in Tables 1, 2 & 3 . The mean time from symptom onset to PCI for the STEMI cohort was 33 ± 19 h. The mean time from symptom onset to PCI for the NSTEMI group was 44 ± 22 h. This difference was not statistically significant. The door to needle time in the STEMI group was 52.9 min.
| STEMI ( n = 17) | NSTEMI ( n = 20) | p value | |
|---|---|---|---|
| Age | 62 ± 8 | 59 ± 10 | 0.22 |
| Male | 12 (71) | 14 (70) | 0.97 |
| BMI | 28 ± 5 | 28 ± 4 | 0.92 |
| Hypertension | 12 (71) | 17 (85) | 0.43 |
| Diabetes | 3 (18) | 3 (15) | 1.00 |
| Dyslipidaemia | 10 (59) | 12 (60) | 0.94 |
| Tobacco use | 12 (71) | 15 (75) | 0.76 |
| Previous PCI | 2 (12) | 1 (5) | 0.58 |
| LVEF | 46 | 57 | <0.01 |
| Adjunctive therapy during PCI | |||
| Aspirin | 17 (100) | 20 (100) | 1.00 |
| Thienopyridine loaded prior to PCI | 17 (100) | 20(100) | 1.00 |
| Glycoprotein IIb/IIIa inhibitor therapy a | 1(6) | 0 | 0.46 |
| Thrombectomy | 4 (24) | 2 (10) | 0.37 |
| Medications at discharge | |||
| Statins | 17 (100) | 16 (80) | 0.11 |
| ACE inhibitor | 13 (77) | 9 (45) | 0.09 |
| B-blocker | 13 (77) | 11 (55) | 0.30 |
a Glycoprotein IIb/IIIa inhibitor therapy was initiated in the cardiac catheterisation laboratory during PCI.
| STEMI ( n = 17) | NSTEMI ( n = 20) | p value | |
|---|---|---|---|
| Target vessel | |||
| LAD | 8 (47) | 10 (50) | 0.86 |
| LCx | 2 (12) | 4 (20) | 0.50 |
| RCA | 7 (41 | 6 (30) | 0.48 |
| Number stents | 1.3 ± 0.5 | 1.3 ± 0.6 | 0.98 |
| Drug eluting stent | 13 (77) | 18 (90) | 0.38 |
| Stent diameter (mm) | 3.31 ± 0.7 | 3.16 ± 0.6 | 0.54 |
| Stent length (mm) | 21 ± 7 | 24 ± 11 | 0.68 |
| Number inflations | 4.9 ± 3 | 5.1 ± 3 | 0.91 |
| Maximum inflation pressure (mm Hg) | 18 ± 3 | 18 ± 4 | 0.98 |
| Post dilation | 15 (88) | 18 (90) | 0.86 |
| STEMI ( n = 17) | NSTEMI ( n = 20) | p value | |
|---|---|---|---|
| Troponin I | 33 ± 22 | 3 ± 5 | <0.001 |
| CK | 1586 ± 1636 | 200 ± 152 | 0.003 |
| Total cholesterol | 4.74 | 4.75 | 0.64 |
| LDL | 2.79 | 3.03 | 0.77 |
| HDL | 1.03 | 1.02 | 0.64 |
| Triglycerides | 1.84 | 1.54 | 0.40 |
| Fasting BSL | 6.10 | 5.53 | 0.09 |
| HbA1c (%) | 5.61 | 5.83 | 0.27 |
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