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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Priyantha Ranaweera [2]; Phone:617-632-7783

Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [3] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Pathophysiology

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 µm) 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

1. Spasm
2. Thromboembolism and distal ischemia

At Cellular/Tissue Level

1. Neutrophil plugging
2. Swelling and edema of endothelial and myocardial cells
3. Capillary leak
4. dead cells develop contraction bands (hypercontraction of myocytes)
5. In the setting of reperfusion – hemorrhage in the interstitium
6. 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

REVERSIBLE AND IRREVERSIBLE COMPONENTS OF THE MICROVASCULAR DYSFUNCTION

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 DYNAMICS OF 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 FLOW DYNAMICS OF 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)

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 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)

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 α-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)

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)

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

http://www.perfuse.org

http://www.timi.org.

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)

=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.

METHOD

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)

METHODS USED TO IMPROVE MYOCARDIAL TISSUE LEVEL PERFUSION

MANAGEMENT OF CRITICAL MYOCARDIAL ISCHEMIA – SYSTEMIC PHARMACOLOGY AND CATHETER BASED INTERVENTIONS

Discussed elsewhere (Hyperlink)

MECHANICAL DEVICES DESIGNED TO PREVENT THROMBO-EMBOLIZATION

Discussed elsewhere (Hyperlink)

INTRACORANRY PHARMACOTHERAPY

The main aim is to improve and re-establish effective tissue level perfusion, prior to irreversible changes are triggered.

Emphasis is to deliver the drug in the highest possible concentration to the affected area thus potentially minimizing systemic effects and ensuring drug delivery to the affected area in coronary slow-flow or no-reflow states.

Administration via the guiding catheter may not achieve adequate dosing because of reflux of drug into the aorta. Ideally they should be administered to the distal vascular bed through a catheter such as a balloon catheter or an ultrafuse catheter.

Glycoprotein 2b3a Inhibitors Eptifibatide

VASODILATORS

NON-ENDOTHELIUM DEPENDENT VASODILATORS

Do not require an intact endothelium for vasodilation

MECHANISM OF ACTION

These compounds contribute active NO (nitric oxide) a vasodilator.

Figure 8 Source: http://www.mayoclinicproceedings.com/

NITROGLYCERIN

Dilates veins, larger arteries and arterioles.

Has an antiplatelet action in-vitro

When administered systemically Venodilation > arterial dilation

Exact mechanism of the action of ic nitroglycerin not fully understood.

Anti anginal response may be mediated systemically rather than locally. This effect should be differentiated from direct coronary vasodilatory properties.(46)

DURATION OF ACTION

Few minutes

CLINICAL EFFECTS OF IC NITROGLYCERIN

Dilates arteries > 100 mcg, including the areas of stenosis, In higher doses dilates larger arteries as well.

Does not cause “steal” phenomenon (As opposed to dipyridamole) (47, 48)

In one study, increased normal luminal area of coronary arteries increased by an average of 28% and luminal area in significantly stenotic segments by 29 %. (49)

Smaller coronary arteries (< 1mm diameter) were shown to have a larger percentage dilation compared to larger arteries when given iv or ic. (50,51)

Pretreatment with intracoronary nitroglycerin prevented exercise-induced vasoconstriction of stenotic coronary arteries. (52)

Intra coronary nitroglycerin has been shown to relieve resistant coronary artery spasm not responding to sub lingual nitroglycerin (53)

CLINICAL USE

Most commonly used ic vasodilator. For suspected or obvious spasm For no-reflow As prophylaxis prior to stenting As prophylaxis in lesions prone to distal embolization. In conjunction with distal emboli-protection Post PCI angina

IC BOLUS

50 – 1000 mcg in boluses

SIDE EFFECTS

Hypotension Headache

REVERSING THE EFFECTS

Hypotension – iv fluids, occasionally inotropes (Eg dopamine)

CORONARY SPASM RESISTANT TO NITROGLYCEINE

There have been reports of spasm unresponsive to ic nitroglycerine (200 mcg – 2000 mcg over 10 mts) being successfully treated with ic verapamil (1000 mcg to 1500 mcg given over 10 mts) (54,55)

SODIUM NITROPRUSSIDE=

Compared with adenosine, intracoronary nitroprusside produces an equivalent but more prolonged coronary hyperemic response in normal coronary arteries (57)

DURATIN OF ACTION =

Minutes (half life = 2 mts)

CLINICAL EFFECTS OF IC NITROPRUSSIDE

50 mcg ic was shown to be effective in alleviating impaired blood flow and no-reflow associated with PCI. (58)

200 mcg produced improved CTFCs among patients with no-reflow and was also associated with a lower incidence of hypotension and bradycardia. (59)

CLINICAL USE

For suspected or obvious spasm For no-reflow As prophylaxis prior to stenting As prophylaxis in lesions prone to distal embolization. In conjunction with distal emboli-protection Post PCI angina

IC BOLUS

100 mcg IC as a single dose to a total dose of 1000 mcg (1 mg)

SIDE EFFECTS

Compared to nitroglycerin, lower incidence of bradycardia, hypotension

ADENOSINE

Synthesized in the myocardium in vivo.

Intravenous or intracoronary adenosine can reliably increase coronary hyperemia to

maximal levels to or even exceeding what is produced by transient ischemia.

MECHANISM OF ACTION

Increases arterial endothelial cell nitric oxide (NO) through adenosine A2a receptors on the myocytes of resistance vessels.  vasodilatation.

Low doses ---> effects are confined to subendocardial vessels. High doses ---> transmural vasodilation (60) Reduces endothelial injury Reduces neutrophil activation (61)

DURATION OF ACTION

Very brief (5-30 seconds).

=AMISTAD I=

Largest randomized trials with Adenosine. How ever the drug was given intravenously.

Patients with STE MI treated with thrombolysis given an infusion of iv 70 mcg/kg/min adenosine infusion, was associated with a significant reduction in infarct size. (62)

=AMISTAD II=

Largest trial (n=2118) (63)

Patients with anterior ST elevation myocardial infarctions treated with either thrombolysis (60%) or primary PCI (40%) received intra venous adenosine 50 mcg/kg/min, 70 mcg/kg/min or placebo

composite primary end point (death, new congestive heart failure or the first re-hospitalisation for congestive heart failure) - no reduction secondary point (infarct size) - trend toward a reduction - did not reach statistical significance

The dose used in these two trials was low compared the conventional dose of 140 mcg/kg/min for coronary hyperemia. Also the drug was delivered systemically.

IC ADENSOSINE AND CLINICAL EFFECTS

Intra coronary adenosine was shown to improve TIMI frame count measurements in patients with microvascular angina. (64)

high-dose intracoronary adenosine in the setting of AMI, has shown to be associated with improved echocardiographic parameters and clinical outcomes. (65)

Several small studies showed an improved microvascular function and reduction in infarct size in the setting of AMI (66,67)

In the setting of ACS ic adenosine compared to saline was shown to significantly improve left ventricular wall motion and coronary flow.(68)

In a canine model, submaximal dosing did not affect the endocardial to-epicardial blood flow ratio, whereas submaximal doses showed a marked preferential endocardial perfusion. (69)

IC DOSING

The dose needed to induce maximum hyperemia was 16 mcg IC for the left coronary artery and 12 mcg IC for the right coronary artery in a subjects with no CAD. (70)

How ever in patients with known CAD, the dose varied from 50 mcg to 800 mcg. With increasing dose > 200 mcg, heart block was increasingly encountered. The ic does of 80 mcg/kg/min produced maximum hyperemia. With higher doses up to 240 mcg/kg/min there was minimal drop in blood pressure but there was no tachycardia. (71)

In a study comparing various doses of IC adenosine, IV adenosine, ATP and papavarine, it was shown that the IC dose and the iv doses produced comparable vasodilation. How ever IV dosing was associated with more episodes of hypotensions and tachycardia and the IC dosing was more less likely to cause tachycardia. Additionally the ic dosing had a propensity to cause bradycardia.

(Bernard De Bruyne, MD, PhD; Nico H.J. Pijls, et al, Intracoronary and Intravenous Adenosine 5'-Triphosphate, Adenosine, Papaverine, and Contrast Medium to AssessFractional Flow Reserve in HumansCirculation. 2003;107:1877-1883.)

IC BOLUS

In healthy persons 16 mcg boluses induced maximal hypermeia. How ever it may be necessary administer larger doses in patients with microvascular dysfunction. (72)

Range used in studies 16 mcg - 4 mg boluses

Usually used : 100 mcg boluses to a total dose of 4000 mcg, (73)

IC INFUSION

10-70 mcg/kg/min with some suggestion that the higher infusion rate may be better

Adenosine has a half-life is 6 seconds. Therefore it can be repeatedly administered when ECG, pulse and blood pressure normalize. (74, 75)

PREPARATION

Add 6 mg of Adenosine to 9 cc of 0.9% NNrmal saline making 600 mcg/ml of the drug. Take 1 cc of this solution and dilute it with 9 cc of normal saline making 60 mcg/ml. Take 1 cc and add 0.9% N saline up to 10 cc yielding 6 mcg ml. Administer paying close attention to the ECG.

Immediately before and during administration electrocardiogram can be recorded at a faster speed (100 mm/sec) to assess changes in the PR, QRS, and QT intervals.

Because transient bradycardia can occur, consideration should be given to the prophylactic placement of a temporary pacemaker.

SIDE EFFECTS

Bradycardia seen with higher doses. By increasing the refractory period of the sinoatrial and atrioventricular nodes produces heart block.

Difficulty in breathing – Uncommon unlike with iv use Hypotension – Uncommon unlike with iv use Tachycardia – Uncommon unlike with iv use Chest pressure – Uncommon unlike with iv use (76, 77)

REVERSING THE EFFECTS

This is not an issue due to short duration of action

DIPYRIDAMOLE

MECHANISM OF ACTION

Increase interstitial adenosine  vasodilation Thought to divert blood to smaller vessels causing “steeling” from the ischemic areas ( as opposed to nitrates)

DURATION OF ACTION

30 mts

CLINICAL USE

Not used due to the availability of its active form, adenosine. How ever if needed the clinical usage could be similar to Adenosine.

REVERSING THE EFFECTS

Methyl xanthines

CALCIUM CHANNEL BLOKCERS (CCB)

NICARDIPINE

MECHANISM OF ACTION

Compared to nifedipine, diltiazem and verapamil, nicardipine was the most vascular smooth muscle selective.

Nicardipine was also shown to be more specific for coronary arteries than peripheral arteries. (78)

DURATIN OF ACTION

5-6 minutes

CLINICAL EFFECTS OF IC NICARDIPINE

After intra venous administration of nicardipine, coronary blood flow increased significantly and the mean aortic pressure decreased by 10% (79)

ic nicardipine 200 µg, 10,000 µg diltiazem and verapamil 200 µg were studied on coronary arteries. The effect on epicardial coronary artery diameter was similar among the 3 calcium channel blockers. Two patients who received diltiazem had a transient episode of type 1 second-degree atrioventricular block. Compared to the other two, nicardipine was shown to significantly increase icoronary blood flow velocity and also had a longer duration of effect (5–6 minutes). (80)

Nicardpine 200 mcg ic not only prevented exercise induced vasoconstriction in the atherosclerotic arteries, but also caused vasodilation, in similar proportions to iv administration.

The combination of nitroglycerin and nicardipine has an additive dilatory effect on coronary arteries that is more pronounced in stenotic than nonstenotic vessels (81, 82)

In patients undergoing PTCA, ic infusion of nicardipine protected the myocardium from regional ischemia, allowing a faster recovery of aerobic metabolism after reperfusion. This mechanism appeared unrelated to direct hemodynamic effects of nicardipine. (83)

in contrast to other calcium antagonists such as nifedipine, which depresses myocardial contractility, nicardipine 200 mcg ic, had negligible effects on myocardial contractility. (84)

CLINICAL USE

For suspected or obvious spasm For no-reflow As prophylaxis prior to stenting As prophylaxis prior to PCI in lesions prone to distal embolization. As prophylaxis with rotational atherectomy As part of the flush irrigation of rotational atherectomy In conjunction with distal emboli-protection Post PCI angina

IC BOLUS

200 mcg as a single dose to a total dose of 1000 mcg (1 mg)

SIDE EFFECTS

Lower incidence of bradycardia and hypotension – therefore may be preferable in patients with low blood pressure.

ic nicardipine has minimal systemic or direct myocardial depressant effects (85)

REVERSING THE EFFECTS

Not usually and issue

NON DIHYDROPYRIDINE CCB

MECHANISM OF ACTION

Blocks L-type calcium channels (vascular smooth muscle, cardiac myocytes, and cardiac sinoatrial and atrioventricular nodes).  block influx of calcium into muscle cells,  smooth muscle, cardiac myocyte relaxation and a-v slowing.

DILTIAZEM=

CLINICAL EFFECTS OF IC DILTIAZEM

Ic administration was shown to prevent exercise induced vasoconstriction of stenotic coronary arteries. (86)

CLINICAL USE

Given the ready availability of Nicardipine, the use of Diltiazem is waning. If needed the clinical usage could be similar to Nicardpine.

IC BOLUS

Diltiazem 200 mcg as a single dose to a total dose of 1000 mcg (1 mg)

PREPARATION

Take 5 mg of Diltiazem in to 9 cc of Normal saline making 500 mcg/ml. Half a ml makes 250 mcg.

SIDE EFFECTS

Bradycardia, hypotension, Myocardial depression

VERAPAMIL

CLINICAL EFFECTS OF IC VERAPAMIL

Was shown to improve TIMI flow rates and TIMI frame counts in patients with CAD Improves angiographic out comes in no reflow states.(87)

Has been shown to augment postinterventional coronary blood flow. (88, 89)

In patients undergoing PCI < 12 hrs of AMI, early administration of intracoronary verapamil 50-100 mcg prior and the same dose during PCI improved postprocedural myocardial perfusion as evaluated by TMPG (90)

In the VAPOR trial, intragraft administration of 200 mcg verapamil prior to saphenous vein graft PCI reduced no-reflow and was associated with a trend toward improved myocardial perfusion. (91)

Compared to those treated with PTCA alone, verapamil 500 mcg ic after primary PTCA improved microvascular function, leading to better LV functional outcome in patients with AMI (92)

Vasospasm distal to a PTCA site may be resistant to nitroglycerine and was shown respond to Verapamil 100 mcg. (93)

In the setting of ACS, 500 mcg of ic verapamil compared to saline was shown to significantly improve wall motion and coronary flow.(68)

Was shown to safely terminate reperfusion-induced ventricular tachyarrhythmias in a rapid manner. However, this effect was not seen for reperfusion-induced VF. (94)

CLINICAL USE

Due to ready availability of Nicardipine, this drug is less commonly used. How ever if needed the clinical usage could be similar to Nicardpine.

IC BOLUS

200 mcg as a single dose to a total of 1000 mcg (1 mg)

SIDE EFFECTS

Bradycardia, Hypotension, Decline in contractility of the myocardium

In one study, 500 mcg ic bolus produced a significantly high incidence of hear block and hypotension. The heart block lasted 3 hours. (68)

PAPAVARINE

DURATIN OF ACTION

Peak effect after 30 sec and a total duration of action of less than 2 to 3 min Maximal coronary hyperemia for up to 30 seconds.

CLINICAL USE

Due to its long duration of action and potential for polymorphic VT, it is not commonly used in the coronary circulation

IC DOSING

infusion Vs boluses

IC BOLUS

Total dose that can be given is limited by its relatively slow systemic elimination (half-life, 3-6 hours. 6-12 mg (2mg/ml 0.9% saline) Maximum dosing 30 mg

SIDE EFFECTS

Polymorphic VT - 0.5% incidence Hypotension, may be prolonged due to its longer half life- limiting its use

ALFA BLOCKERS

==CLINICAL EFFECTS OF IC PHENTOLAMINE==

72 hrs following thrombolysis for AMI, alfa-adrenergic blockade ic, using phentolanine attenuated vasoconstriction and postischemic LV dysfunction after PCI.

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 α-blockers.

In this study patients initially received thrombolysis followed by angiography 24 hrs later. Also there was no use of glycoprotein inhibitors. (95)

==CLINICAL USE==

Not commonly used clinically

ENDOTHELIUM DEPENDENT VASODILATORS

Require and intact endothelium. If the endothelium is diseased or absent the paradoxical vasoconstriction occurs.

SUMMARY OF INTRACORONARY PHARMACOTHERAPY

Coupled with the understanding of the importance of preservation of microvascular bed and the inability to progress further on the available systemic pharmacotherapy, there is renewed interest in local drug delivery to achieve higher than usual local drug concentrations.

Commonest of them are vasodilators, out of which the commonest being nitroglycerine. There is some what frequent use of adenosine, and nicardipine though the most of the experience is mainly on adenosine. Use of verapamil and diltiazem are declining due to the availability of nicardipine.

Despite the lack of randomized trials, their use in niche situations such as prevention and treatment of no-reflow is how ever may prove to be life saving.

The evidence on the use of intracoronary glycoprotein inhibitors is sparse. Until more robust data becomes available, regular use of this class of medications is not recommended.

There has been several studies looking at intracoronary thrombolytics. How ever there is no evidence to suggest that they are superior to current therapy.

Future studies are expected to address some of the issues in this arena.

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