TIMI classification in coronary perfusion

# Introduction
Name coronary was coined in the mid 19th century on the belief that there were free arterial anastomoses resembling a corona  latin for crown.
Earliest description of mechanical relief of coronary thrombotic obstruction came form the work of Chazov in 1962 ref1.
Earliest report of intra-coronary drug administration came from Ganz et al when intra coronary (ic) streptokinase was successfully administered to a thrombosed artery ref2.
Thrombolysis in acute myocardial infarction has reduced mortality by 30%.
The main aim at that time was to restore mere luminal patency in the culprit coronary artery.
With the introduction of the normal flow which included the TIMI flow grade, the goal of reperfusion further refined to restoration of normal or TIMI III epicardial blood flow.
TIMI group noted that there was no improvement in left ventricular function after successful thrombolysis. (3)Understanding of "downstream" coronary flow dynamics and its clinical implications followed.
TIMI flow grade was further refined to a corrected TIMI frame count (CTFC).
This was followed by the angiographic observation of a surrogate of tissue level function of the myocardium  the TIMI myocardial perfusion grade (TMPG or TIMI blush grade).
Emphasis thus changed to tissue level preservation of the myocardial milieu.
Many interventions  both pharmacological and mechanical- have been tested in prevention and treatment of this disturbed milieu in the myocardial microvasculature in the setting of ischemia and thromboembolism. What follows is an overview.

# Pathophysiology and sequelae of coronary thrombosis
The process of coronary thrombosis starts at a ruptured or fissured plaque creating an in-situ platelet and fibrin aggregate which progresses to an occlusive thrombus.
There is also dissemination of platelet rich thrombi down stream which cause micro vascular obstruction and tissue level myocardial ischemia.
This leads to coronary microvascular dysfunction, ( ie: disordered function of the smaller coronary resistance vessels (< 100-200 m) which are not seen on coronary angiography.
There are also multiple humoral factors which play a role in setting up the cascade of reversible and irreversible damage at cellular and ultra-structural level.
This leads to

## At macrovascular level
Spasm

## At microvascular level
- vasoconstriction
- Thromboembolism and distal ischemia

## At cellular level
- Neutrophil plugging
- Swelling and edema of endothelial and myocardial cells
- Capillary leak
- In the setting of reperfusion  hemorrhage in the interstitium
- myocytolysis (large vacuoles in cells)  and cell death and removal of dead cells by macrophages, with the beginning of vascular granulation tissue formation  followed by repair-granulation tissue, becoming more fibrous and less vascular over time

## At ultra-structural level
- dead cells develop contraction bands (hypercontraction of myocytes)
Clinically TIMI flow rate, CTFC, TMPG, ECG, LVEF all complement each other in their reflection of the state of the affected myocardium.
In the acute setting, apart from the ECG, there are no indicators to differentiate myocardial reversibility from irreversibility.

### Pathophysiology of reversible flow changes in the microvasculature
1.Heightened downstream microvascular obstruction
1.1.alpha adrenergic neural reflexes,
1.2.spasm due to other causes
1.3.thrombotic occlusion of microvessels.

### Pathophysiology of irreversible changes in the microvasculature
1.capillary leak  advanced stages
2.interstitial hemorrhage
3.Cell death
4.Fibrosis

# TIMI CLASSIFICATION AND OPEN MUSCLE HYPOTHESIS  AN OVERVIEW

## THE OPEN ARTERY CONCEPT AND THE TIMI FLOW RATE
Patients with a patent infarct related artery 90 minutes after the start of thrombolytic therapy, there was a lower 6 month (5.6% vs. 12.5%) and 1 year mortality (8.1% vs. 14.8%). (4)
(Figure 1  Source :    )(4)
For patients with both early and sustained patency through hospital discharge, the subsequent mortality was 3.8% at 1 year. (4)
More studies confirmed that early reperfusion decreased infarct size, improved left ventricular function and survival. (5,6)

### TIMI FLOW GRADE
In order to evaluate the coronary reperfusion more accurately and in a reproducible manner, a grading system of was developed initially for use in the TIMI 1 trial. This has subsequently been adopted almost universally.
TIMI grade 0 - complete occlusion of the coronary artery
TIMI grade 1 -  some penetration of the obstruction by contrast material, but no perfusion of the distal coronary bed.
TIMI grade 2 - perfusion of the entire coronary artery, but with delayed flow compared to a normal artery
TIMI grade 3 - flow denotes full perfusion with normal flow.

### TIMI FLOW IN ACUTE STE MI
In the TIMI 1 trail, patients with TIMI grade 3 flow at 90 minutes of thrombolytic therapy had the lowest mortality, 4.7%, compared to 7.0% and nearly11% for patients with TIMI grade 2 flow and TIMI grade 0 - 1 flow respectively. (8)

### TIMI FLOW IN UNSTABLE ANGINA
Faster flow was shown to be associated with improved clinical outcomes both in the acute MI setting and in the setting of unstable angina following percutaneous coronary intervention. (9,10,11)
(Figure 2).

## CORRECTED TIMI FRAME COUNT  CTFC
limitations with TIMI grading of coronary blood flow is the relative lack of reproducibility between angiographers with one study, showing an agreement of TIMI grade 3 flow of 71%. (12)
This was addressed with the development of a quantitative assessment  the TIMI frame count  which was based on the number of angiographic frames needed for dye to traverse the artery. (13)
This is a measure of time and it does not account for vessel length or volume, and is only an index of coronary velocity and flow.
CTFC has been shown to be reproducible, with a coefficient of correlation of .0.95 between observers and differences between observers of 2 frames . French et al. reported mean differences between observers of 0.75 frames. (14,15,16,17)

### TIMI 4 FLOW
Within the group with TIMI III  flow, there is a group of patients with even faster (a TIMI frame count < 14) than normal flow (hyperemic flow)
Patients with this flow have even better outcomes than those patients with slower TIMI grade 3 flow. In order to have hyperemic flow, the integrity of the microvasculature must be better preserved when compared to the rest of the patient cohort. (18)(Figure 2).
(Figure 3  Even faster epicardial flow is related to better outcomes)

## BLOOD FLOW IN NON CULPRIT ARTERIES DURING ACS
both in acute MI and in the setting of unstable angina epicardical coronary flow was abnormal also in the non culprit arteries (by 40% in the setting of acute MI). (normally 21 frames for dye to traverse an epicardial artery in the absence of acute MI, flow in uninvolved arteries is slowed to over 30 frames)
In a quarter of cases, flow in the uninvolved artery was actually slower than the culprit artery. (19, 20)
(Figure 4 Acute MI slows blood flow globally)

## FLOW FOLLOWING PCI  ACUTE MI
The flow following PCI for acute MI was often the same as that in non-culprit arteries: over 30 frames13
PCI improved culprit TIMI frame count by 6 frames  9 frames short of being normal  a consequence of a disturbed milieu at tissue level.
Slower global flow in all three arteries was also associated with a higher risk of adverse outcomes including mortality compared to those who had normal flow in non culprit arteries.
In one study, flow in the uninvolved artery improved following PCI of the culprit artery significantly (by nearly 10 frames) if it was abnormal to begin with.
After 15 minutes of observation, however, flow in both the culprit and non-culprit arteries again slowed back down to pre-intervention values  which was re-restored after administration of -blockers. - In this study patients initially received thrombolysis followed by angiography 24 hrs later. Also there was no use of glycoprotein inhibitors. (21,22)

## STENTING AND CTFC
In the PAMI stent trial, compared with conventional primary angioplasty, stenting reduced restenosis. How ever one month and six-month mortality were higher among stented patients, (specially  with a closed vessel preceding PCI). Suggesting the possibility that stenting may have irreversibly disturbed the distal vascular bed, probably by increasing downstream embolization of atheroembolic particles. Also the stenting process may have generated more humoral factors some of which may have been reversible - producing undesirable effects. (23,24)

## RESIDUAL STENOSIS AND MORTALTY
Even though the residual stenosis was only 16% following adjunctive stent placement, normal flow was still not restored in up to one-third of patients  a group with significantly higher mortality. This is highly unlikely to be due to the minimal residual stenosis. (25)
IV nitrates following thrombolytic administration was shown to slow the CTFC (increase transit time down the artery). How ever overall flow in was preserved. (26)

### IS BIGGER THE BETTER WITH STENTING?
It has also been shown that larger stent sizes were associated with a higher risk of slower flow. (27 ref pending)

## CTFC AND LONG TERM SURVIVAL=
French et al, reported CTFC after myocardial infarction was an independent predictor of 5-year survival, but was not superior to TIMI flow grading. Neither factor independently influenced 10-year survival. (28)

## CTFC COMPARED TO OTHER PROGNOSTICATORS

# CFR
Maginas et al, showed that the CTFC, could be used reliably in the catheterization laboratory to estimate CFR. (29)
CTFC used in the context of a ratio with minimal luminal diameter, before and after adenosine was shown to be highly correlated with coronary flow reserve (CFR) as assessed using a Doppler velocity wire (r=0.88). (30)

### TIMI FRAME COUNT IN ESTIMATING CORONARY BLOOD FLOW
The combination of quantitative coronary angiography and the TIMI frame count could be used to integrate velocity and volume measurements to estimate coronary blood flow.
Potentially these methods could be automated to provide estimates of absolute coronary blood flow in the cardiac catheterization laboratory. (31)

## BEYOND THE EPICARDIAL VESSEL  REACHING FOR THE MICROVASCULATURE MILIEU

## MICROEMBOLISATION IN TO THE DISTAL VASCULAR BED
Small areas of myocardial necrosis due to emboli likely from a ruptured plaque were first demonstrated on post mortem analysis Falk in a post mortem analysis, which was subsequently confirmed in-vivo by Gibson et al. (32)

### MYOCARDIAL CONTRAST ECHOCARDIOGRPHY
With no reflow, microbubbles do not enter the myocardium where there is a higher risk of arrhythmia, congestive heart failure, or death.
This technique is limited for routine clinical application due to the need of additional equipment, personnel, time and expense. (33)

## TIMI MYOCARDIAL PERFUSION GRADE / BLUSH GRADE (TMPG)=
A simple semi-quantitative technique that could be conveniently and reliably applied in the cardiac catheterization laboratory, enabling the angiographer to assess tissue level perfusion from the angiogram alone. (34)
Figure 4 : video demonstration can be seen at

## CORRELATION OF TMPG TO OTHER MODALITIES IN ASSESSING MICROVASCULATURE =
TMPG was strongly related to i.v. myocardial contrast echocardiography (MCE) and CFR using iv adenosine.
Patients with normal myocardial blush also have improved wall motion on echocardiography. (35)

### TIMI MYOCARDIAL PERFUSION GRADES

### =NORMAL MYOCARDIUM  GRADE 3
Normal ground glass appearance of myocardial blush diffusely, and at the end of the washout phase, dye is only mildly persistent or is gone.

### MILDLY IMPAIRED TISSUE LEVEL PERFUSION  GRADE 2=
Dye enters the myocardium, but accumulates and exits more slowly. At the end of the washout phase, dye in the myocardium is strongly persistent.

### MODERATELY IMPAIRED TISSUE LEVEL PERFUSION - GRADE 1
The dye does not leave the myocardium and there is a stain on the next injection.

### SEVERELY IMPAIRED TISSUE LEVEL PERFUSION  GRADE 0=
Dye does not enter the myocardium and there is minimal or no blush apparent during the injection and washout phases.

## TMPG - SHORT TERM OUTCOMES
In patients treated with thrombolysis, normal TIMI myocardial perfusion grade 3 flow was associated with improved mortality. (36) (Figure)
(Figure 5 TMP grades)

## DOES TMPG GRADING ADD INFORMATION BEYOND TIMI FLOW GRADING ?
Patients with TIMI grade 3 flow in the epicardial artery who had a closed microvasculature (TMPG 0/1 flow) had a higher mortality (5.4%) than those with TMPG 2 (2.9%) or TMPG 3 flow (0.7%)(p=0.007)(Figure).
Even among patients with TIMI grade 3 flow, there was a 7-fold increase in mortality dictated independently by the extent of the TMP grading. TIMI myocardial perfusion grade was a predictor of 30-day mortality, independent of gender, age, admission pulse, anterior MI location, the TIMI frame count, and the TIMI flow grade. (37)

## TMPG - LONG TERM OUTCOMS
For patients who had thrombolytic therapy for STEMI, at 2 years following thrombolytic therapy, the TMPG was a multivariate predictor of mortality, independent of flow in the epicardial artery. (36)
(Figure 6 TMPG and mortality)

## TMPG IN THE SETTING OF EMERGENCT PCI
TMPG was a more potent and accurate predictor of survival than was TIMI flow alone after acute infarct PTCA
Interventions which normalize myocardial blush may in fact reduce mortality.
Interestingly only ~30% of pts undergoing PTCA had normal myocardial blush restored (38)

## TMPG IN THE SETTING OF OTHER KNOWN PROGNOSTICATORS

### ECG
Among patients with epicardial TIMI grade 3 flow, improved flow in the microvasculature by the TMPG method is also associated with improved EKG resolution by the Schroeder criteria. (39)
In acute STE MI, restoration of flow associated with TMPG 3 was shown to be associated with higher rates of complete ST resolution on the static ECG. It was also a predictor of rapidity of achieving the time to stable ST-segment resolution by a factor of two. (40)
Though the ECG and the TMBG are associated, they provide independent and complimentary prognostic information about infarct size (41)

### LEUKOCYTOSIS DURING ACUTE MI
Leukocytosis may not only be an association but also portends a poorer prognosis.
Leucocytosis was associated with reduced epicardial blood flow, myocardial perfusion thromboresistance (arteries open later and have a greater thrombus burden),and a higher incidence of new congestive heart failure and death, the development of which was independent of coronary blood flow and other covariates. (42)

## TMPG USING DSA
By using digital subtraction angiography (DSA) further refinement of the interpretation of TMPG is possible.
(Figure 7 Computerized DSA imaging of TMPG)
A background image is created by saving an image before dye fills the myocardium which contains an image of the ribs, spine, lung and the artery itself. An image is then stored from several heart beats later, at a time when dye has filled the myocardium - the blush image. The  background image is then subtracted from the blush image to remove the unwanted obtrusive structures isolating a picture of the dye in the heart muscle. The brightness of the blush, the size of the blush and the time it took for the blush to attain that size and brightness is measured. ECG gating is used to minimize motion artefacts.
This technique showed glycoprotein IIb/IIIa inhibition with eptifibatide to be associated with more rapid filling of the myocardium with a larger blush with improved coronary flow reserve, in the setting of unstable angina and stenting. It was also shown that TMPG grades 0-2 were associated with increased CK release and higher clinical event rates. (43)

# The five laws as suggested by Gibson, governing the time-dependent open vasculature hypothesis
1 Not all TIMI grade 3 flow is created equally
2. TIMI grade 3 flow is necessary but not sufficient
3. It is the restoration of normal tissue level reperfusion that optimized outcomes
4. Time is myocardium: faster restoration of flow is related to improved clinical outcomes (44)
5. Sustained flow and the absence of re-occlusion is related to improved outcomes(45)

# Resource
- ref1 PMID 15541835