Use of the TIMI frame count in the assessment of coronary artery blood flow and microvascular function over the past 15 years.

Since its introduction, the TIMI frame count method has contributed to the understanding of the pathophysiology of coronary artery disease. In this article, the evolution of the TFC method and its applicability in the assessment of various therapeutic modalities are described.

Impact of iodinated contrast injections on percent diameter coronary arterial stenosis and implications for trials of intracoronary pharmacotherapies in patients with ST-elevation myocardial infarction.

Administration of fibrinolytic, antiplatelet, and antithrombotic agents by the intracoronary route may disaggregate clot, but the potential role of the mechanical force of the injection itself in decreasing clot burden has not been studied. Patients with ST-segment elevation myocardial infarction who were pretreated in the emergency room (ER) with unfractionated heparin and aspirin in the TITAN-TIMI 34 study were randomized to treatment with eptifibatide in the ER (n = 131) versus after diagnostic catheterization (n = 150). Quantitative coronary angiography was used to assess change in diameter stenosis from time of first contrast injection to injection before percutaneous coronary intervention (PCI) immediately preceding wire placement down the culprit artery in a matching view. Successful perfusion of the myocardium was assessed after PCI by the presence of Thrombolysis In Myocardial Infarction myocardial perfusion grade of 2 or 3. In patients treated with eptifibatide in the ER, there was a 1.3% absolute improvement in diameter stenosis from the first injection to the injection before PCI (p = 0.02), whereas there was no change in diameter stenosis in patients not treated with eptifibatide in the ER (0.0%, p = NS). Each 1% improvement in percent diameter stenosis during diagnostic injections before PCI was strongly correlated with an open muscle after PCI (adjusted odds ratio 1.09, 95% confidence interval 1.02 to 1.16, p = 0.012). In conclusion, the mechanical force of a contrast injection decreases thrombotic burden in patients with ST-segment elevation myocardial infarction pretreated with eptifibatide but not with placebo. Future trials of intracoronary pharmacotherapies should include a control arm in which saline is injected to account for the potential clot disaggregation that occurs as a result of iodinated contrast injections, particularly if the patient has been pretreated with aggressive pharmacotherapy.

Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction.

BACKGROUND: Although 90-minute TIMI flow grades (TFGs), corrected TIMI frame counts (CTFCs), and TIMI myocardial perfusion grades (TMPGs) have been associated with 30-day outcomes, we hypothesized that these indices would be related to long-term outcomes after thrombolytic administration. METHODS AND RESULTS: As a substudy of the TIMI 10B trial (tissue plasminogen activator versus tenecteplase), 49 centers carried out 2-year follow-up. TIMI grade 2/3 flow (Cox hazard ratio [HR] 0.41, P=0.001), reduced CTFCs (faster flow, P=0.02), and an open microvasculature (TMPG 2/3) (HR 0.51, P=0.038) were all associated with improved 2-year survival. Rescue percutaneous coronary intervention (PCI) of closed arteries (TFG 0/1) at 90 minutes was associated with reduced mortality (P=0.03), and mortality trended lower with adjunctive PCI of open (TFG 2/3) arteries (P=0.11). In a multivariate model correcting for previously identified correlates of mortality (age, sex, pulse, left anterior descending coronary artery infarction, and any PCI during initial hospitalization), patency (TFG 2/3) (HR 0.32, P<0.001), CTFC (P=0.01), and TMPG 2/3 remained associated with reduced mortality (HR 0.46, P=0.02). CONCLUSIONS: Both improved epicardial flow (TFG 2/3 and low CTFCs) and tissue-level perfusion (TMPG 2/3) at 90 minutes after thrombolytic administration are independently associated with improved 2-year survival, suggesting complementary mechanisms of improved long-term survival. Although rescue PCI reduced long-term mortality, improved microvascular perfusion (TMPG 2/3) before PCI was also related to improved mortality independently of epicardial blood flow and the performance of rescue or adjunctive PCI. Further prospective trials are warranted to re-examine the benefit of early PCI with thrombolysis.

Impact of diabetes mellitus on epicardial and microvascular flow after fibrinolytic therapy.

BACKGROUND: Patients with diabetes are at increased risk of death after acute myocardial infarction, independent of other baseline risk factors and more severe coronary artery disease. We studied the angiographic and electrocardiographic responses to thrombolytic agents in patients with diabetes; in particular ST-segment resolution as a measure of microvascular flow. METHODS: Angiography was performed in 2588 patients at 90 minutes after thrombolytic agent administration as well as after percutaneous coronary intervention (PCI) in the Thrombolysis In Myocardial Infarction (TIMI) 4, 10A, 10B, and 14 trials. Electrocardiographic parameters were assessed at baseline and at 90 minutes in the TIMI 14 trial. RESULTS: Compared with those without diabetes, patients with diabetes (347/2588 [13.4%]) were older, more often female, heavier, and less often smokers, and they had higher systolic blood pressure on admission. At angiography, they more frequently had 3-vessel disease, well-developed collateral vessels, more distal culprit lesions, and smaller reference segment diameters. In the infarct-related artery, there was no relationship between diabetes and TIMI 3 flow at 90 minutes (55.4% vs 59.0% without diabetes) or after PCI, (83.7% vs 84.2%, both P = NS). Corrected TIMI frame counts were also similar at both time points. However, there was less frequent complete ST-segment resolution among diabetic patients after thrombolysis (38.6% vs 49.2%, adjusted P =.04). CONCLUSION: Thrombolysis and adjunctive/rescue PCI achieved equal rates of epicardial flow in patients with and without diabetes. However, diabetic patients had less complete ST-segment resolution, suggesting impaired microvascular flow. Abnormal microvascular flow may contribute at least in part to the poorer outcomes observed in patients with diabetes and acute myocardial infarction.

Correlates of coronary blood flow before and after percutaneous coronary intervention and their relationship to angiographic and clinical outcomes in the RESTORE trial. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis.

BACKGROUND AND OBJECTIVES: Slower blood flow in the setting of acute myocardial infarction (MI) has been related to adverse outcomes, but the relationship of coronary blood flow after percutaneous transluminal coronary angioplasty (PTCA) in the setting of acute coronary syndromes to adverse outcomes and restenosis has not been well described. We sought to evaluate the correlates of pre- and post-PTCA coronary blood flow to shed light on potential modifiable determinants. METHODS: The RESTORE trial (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) was a randomized, double-blind, placebo-controlled trial of tirofiban in patients undergoing balloon angioplasty or directional atherectomy within 72 hours of occurrence of either unstable angina pectoris or acute MI. Coronary blood flow was assessed with the corrected TIMI frame count (CTFC), and clinical outcomes were assessed at 30 days. RESULTS: In addition to tighter and longer minimum lumen diameters (MLDs), the multivariate correlates of slower flow before PTCA also included the presence of thrombus, collaterals, left coronary artery lesion location, acute MI, and >8F catheter size. As well as the above variables, type C and D dissection grades were related to slower post-PTCA CTFC. Death, or the composite of death/MI/coronary artery bypass graft at 30 days, was more frequent among patients with slower post-PTCA CTFCs and those with post-PTCA thrombus. In a multivariate model correcting for reference segment diameter and MLD, the post-PTCA CTFC was an independent predictor of late lumen loss and the follow-up MLD at 6 months. As a single index that integrates functional and anatomical aspects of the post-PTCA results, the ratio of CTFC/MLD was associated with death/MI by 30 days. CONCLUSIONS: In addition to MLD, variables such as the presence of thrombus, left coronary artery lesion location, and dissection grade also are associated with slower coronary blood flow after PTCA. In turn, post-PTCA CTFCs were an independent predictor of late lumen loss and follow-up MLDs. Furthermore, patients who die or who sustain other adverse cardiac events have slower coronary blood flow and greater thrombus burden after PTCA.

Relationship of creatine kinase-myocardial band release to Thrombolysis in Myocardial Infarction perfusion grade after intracoronary stent placement: an ESPRIT substudy.

BACKGROUND: The etiology of creatine kinase-myocardial band (CK-MB) release after percutaneous coronary intervention (PCI) remains unclear. The goal of this study was to evaluate the relationship of both epicardial and tissue level perfusion at the completion of stent placement to CK-MB release after the procedure. Given the high rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow after PCI, we hypothesized that abnormalities in tissue level perfusion would instead explain CK-MB release. METHODS: Data were drawn from the angiographic substudy of the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trial of eptifibatide versus placebo in patients undergoing planned coronary stent implantation. In the substudy, cinefilms of 65 patients were analyzed by an angiographic core laboratory blinded to enzymatic and clinical outcomes. RESULTS: The release of CK-MB was not associated with TIMI grade 3 flow or the corrected TIMI frame count; 100% of patients had TIMI grade 3 flow at the completion of PCI. In contrast, tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) was related to postintervention CK-MB release: patients with a closed myocardium (TMPG 0/1) or delayed myocardial perfusion (TMPG 2) had an average CK-MB release 2.2 +/- 2.7 times the upper limit of normal (n = 34), whereas those patients with normal myocardial perfusion (TMPG 3, n = 24) had CK-MB 0.8 +/- 0.6 times the upper limit of normal (P =.01). Although no patients with TMPG 3 sustained death/myocardial infarction/urgent target vessel revascularization or thrombotic bailout, 17.7% of patients with TMPG 0/1/2 did by 48 hours (P =.037). CONCLUSIONS: Impaired tissue level perfusion as assessed by the TMPG and not epicardial coronary blood flow is associated with CK-MB elevation after PCI. These data provide a pathophysiologic link between impaired tissue level perfusion, post-PCI infarction, and adverse clinical outcomes.

Association of the Fibonacci Cascade with the distribution of coronary artery lesions responsible for ST-segment elevation myocardial infarction.

This is the first study to demonstrate the appearance of the Fibonacci Cascade within the distribution of coronary artery lesions in the human heart. The propensity for this ratio to appear in nature may also be because this ratio optimizes the efficiency of packing structures in a limited space in such a way that wasted space is minimized and the supply of energy or nutrients is optimized.

Time for contrast material to traverse the epicardial artery and the myocardium in ST-segment elevation acute myocardial infarction versus unstable angina pectoris/non-ST-elevation acute myocardial infarction.

Although the time for contrast material to fill the epicardial artery in the setting of acute coronary syndromes has been studied extensively, the time for contrast material to fill the myocardium has not been evaluated. We compared differences in myocardial contrast material transit among patients with unstable angina pectoris/non-ST-elevation acute myocardial infarction (UAP/NSTEAMI) with patients with ST-elevation acute myocardial infarction (STEAMI). The time it took for contrast material to first appear and to arrive at peak intensity in the myocardium was compared in 224 patients with STEAMI enrolled in the LIMIT-AMI study versus 430 patients with UAP/NSTEAMI enrolled in the TACTICS-TIMI 18 trial. In patients with STEAMI, there was a delay in both the time for contrast material to first enter the myocardium (5,619 +/- 1,789 vs 4,663 +/- 1,626 ms, p <0.0001) and the time from entrance to peak blush intensity (2,387 +/- 1,359 vs 1,959 +/- 1,244 ms, p = 0.003) compared with patients with UAP/NSTEAMI. STEAMI remained significantly associated with impaired entrance of contrast material into the myocardium (p <0.0001) in a multivariate model controlling for known correlates of impaired epicardial flow (presence of thrombus, percent diameter stenosis, left anterior descending artery location, and contrast material inflow in the epicardial artery [corrected TIMI frame count]). The time for contrast material to enter the myocardium is impaired to a greater degree in STEAMI compared with UAP/NSTEAMI, even after adjusting for other variables known to delay flow in the epicardial artery. These data provide insight into potential mechanistic differences between these 2 clinical syndromes.

Transfusion associated microchimerism: a heretofore little-recognized complication following transfusion.

Potent antiplatelet and antithrombotic agents have significantly reduced mortality in the setting of acute coronary syndromes and percutaneous coronary intervention. However these agents are associated with increased bleeding which is in turn associated with adverse clinical outcomes. In many centers, transfusion is often used to correct for blood loss. Blood transfusion in the setting of acute coronary syndrome has been associated with adverse clinical outcomes including increased mortality. Transfusion associated microchimerism (TA-MC) is a newly recognized complication of blood transfusion. There is engraftment of the donor's hematopoietic stem cells in patients who then develop microchimerism. This article discusses the association of bleeding/blood transfusion with adverse outcomes and the potential role of TA-MC in clinical outcomes.

Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction.

Although percutaneous coronary intervention restores optimal epicardial blood flow in most cases, abnormal myocardial perfusion may still persist. This might be as a result of macro and microembolization, neutrophil plugging, vasoconstriction, myocyte contracture, local intracellular and interstitial edema, intramural haemorrhage, and endothelial blistering. Local delivery of intracoronary pharmacotherapy via the coronary arteries may increase local drug concentration several fold, and may improve drug efficacy. Several pharmacological agents such as adenosine, calcium channel blockers, alpha blockers, beta2 receptor activators, vasodilators, antithrombotics, and antiplatelet agents have been used to treat coronary microvascular dysfunction. This article reviews the results of trials of intracoronary pharmacotherapy to date.

Precordial ST-segment depression in inferior myocardial infarction is associated with slow flow in the non-culprit left anterior descending artery.

BACKGROUND: Anterior precordial ST-segment depression (APSTD) is common in the setting of inferior myocardial infarction (IMI). The presence of APSTD correlates with increased risk of adverse outcomes in patients with acute IMI as well as more myocardium at risk as assessed by sestamibi, larger infarcts, lower ejection fractions, and more severe wall motion abnormalities in the infarct region. The ECG leads associated with APSTD (V1-V3) are generally thought to represent electrical activity subtended by the anterior myocardium, which is perfused by the left anterior descending artery (LAD). To determine whether APSTD is associated with abnormal blood flow in the uninvolved or non-culprit LAD, we assessed TIMI flow grades and corrected TIMI frame counts (CTFC) in both the culprit and non-culprit arteries of IMI patients. METHODS: Data were drawn from the TIMI 10B trial of tenecteplase versus front-loaded tissue plasminogen activator in acute MI. Baseline ECGs were obtained within 12 hours of symptom onset, and angiography was performed 90 minutes following thrombolytic administration. A patient was considered to have precordial ST-segment depression if any ST-segment depression was present in any of leads V1-V3. RESULTS: The majority of IMI's were due to right coronary artery occlusions, both in patients with APSTD (79.6%) and without APSTD (77.9%). In patients in whom the LAD was not the culprit artery but with APSTD were significantly less likely to have TIMI 3 flow at 90 minutes and more likely to have TIMI 2 flow. There was a trend toward slower CTFC in APSTD patients (27.2 +/- 13.4 vs. 22.6 +/- 8.5 frames/sec, p = 0.07). CONCLUSIONS: Among patients with acute IMI associated with precordial ST-segment depression, flow in the non-culprit left anterior descending artery was slower than that in patients without APSTD. This finding may partially explain the occurrence of APSTD in IMI.

Methodologic and clinical validation of the TIMI myocardial perfusion grade in acute myocardial infarction.

Improved microvascular perfusion using the TIMI myocardial perfusion grade (TMPG) has been related to reduced in hospital, 30-day and 2-year mortality following thrombolytic administration. We sought to validate this measure using the more quantitative technique of digital subtraction angiography (DSA) and to correlate TMPG with ST segment resolution. DSA was used to analyze films from the LIMIT AMI acute myocardial infarction trial of front loaded r-tPA and rhuMAb CD18. Dye kinetics were also characterized using DSA in 88 arteries from patients without acute coronary syndromes in the absence of an obstructive lesion. Compared to normal patients, microvascular perfusion was reduced in acute myocardial infarction patients on DSA as demonstrated by a reduction in peak Gray (brightness) (p < 0.0001), the rate of rise in Gray/sec (p < 0.0001), the blush circumference (p < 0.0001), and the rate of growth in circumference (cm/sec) (p < 0.0001). However, while DSA perfusion was impaired overall in the setting of acute myocardial infarction, TMPG grade 3 in the setting of acute myocardial infarction did not differ from that in normal patients when studied quantitatively as shown by similar rates of growth in brightness and circumference (p = NS). ST resolution and the TMPG were significantly associated (p = 0.04). Compared to normal patients, acute myocardial infarction reduces the peak brightness of the myocardium, the rate of rise in brightness, the circumference of blush and the rate of growth in circumference as assessed using digital subtraction angiography. However, acute myocardial infarction patients with TMPG 3 had rates of growth in brightness and circumference that were nearly identical to normal patients. Thus, DSA validates that TMPG 3 is associated with normal kinetics of myocardial perfusion, and this likely accounts for the low (0.7%) 30 day mortality observed among those patients with TFG 3 and TMPG 3.