2. DEFINITION
The phenomenon of no-reflow is defined as inadequate
myocardial perfusion through a given segment of the coronary
circulation without angiographic evidence of mechanical vessel
obstruction.
3. No-reflow has been documented in ≥ 30% of patients after
thrombolysis or mechanical intervention for acute myocardial
infarction.
4. Patients with No-Reflow exhibit a higher prevalence of: early
postinfarction complications (arrhythmias, pericardial effusion,
cardiac tamponade, early congestive heart failure).
Left adverse ventricular remodeling
Late repeat hospital stays for heart failure.
Mortality.
5. HISTORY
The first clinical observation of coronary no-reflow was
reported by Schofer et al.in 1985.
In 1989, Wilson et al. observed persistent angina with ST
elevation in association with a slow angiographic antegrade
flow despite a widely patent angioplasty site in five patients
immediately after PTCA of a thrombus containing lesion.
In 1991,Pomerantz et al. reported five more cases of no-
reflow successfully treated by intracoronary verapamil.
The first clinical case of no-reflow during PTCA for acute
myocardial infarction was reported by Feld et al. in1992.
7. No-reflow can be categorized as sustained and reversible.
Sustained no-reflow is probably the result of anatomical
irreversible changes of coronary microcirculation.
Reversible No-reflow is the result of functional and
thus reversible changes of microcirculation.
8. Pathophysiology of
No Reflow
No reflow results from obstruction of the myocardial
microcirculation, defined as vessels 200 m in diameter.
Preexisting microvascular dysfunction may exacerbate the
degree of microvascular obstruction that develops after both
elective and infarct-related PCI.
9.
10. In humans, no-reflow is caused by the variable combination of 4
pathogenetic components:
1) Distal Atherothrombotic Embolization
2) Ischemic Injury
3) Reperfusion Injury
4) Susceptibility Of Coronary Microcirculation To Injury
11. Distal embolization
Emboli of different sizes can
originate from epicardial coronary
thrombus and from fissured
atherosclerotic plaques, in
particular during PPCI.
Experimental observations have
shown ,that myocardial blood flow
decreases irreversibly, when
microspheres obstruct more than
50 % of coronary capillaries.
12. Ischemia-related injury
Changes in endothelial cells, visible after prolonged ischemia, are
represented by endothelial protrusions and membrane-bound bodies,
which often fill the capillaries up to luminal obliteration.
Furthermore, large endothelial gaps with extra vascular erythrocytes
are common . Morphological findings are accompanied by a
reduction of regional myocardial blood flow within the previously
ischemic region .
Moreover, myocardial cell swelling associated with interstitial edema
might cause microvascular compression
13. A massive infiltration of coronary microcirculation by
neutrophils and platelets occurs at the time of reperfusion.
14. Reperfusion-related injury
Sustained vasoconstriction of coronary microcirculation Neutrophils also
form aggregates with platelets, that plug capillaries, thus mechanically
blocking flow.
Finally, vasoconstriction released by damaged endothelial cells, neutrophils,
and platelets
Tissue and endothelial damage
Release of oxygen free radicals, proteolytic enzymes, and pro-inflammatory
mediators
Subsequent adhesion to the endothelial surface and migration in the
surrounding tissue
Massive infiltration of coronary microcirculation by neutrophils and platelet
at the time of reperfusion
15. Predictors of Pathogenic Components of No -Reflow
• Thrombus burden
Distal
embolization
• Ischemia duration
• Ischemia extent
Ischemia
• Neutrophil count
• ET-1 levels
• TXA2 levels
• Mean platelet volume or reactivity
Reperfusion
• Diabetes
• Acute hyperglycemia
• Hypercholesterolemia
• Lack of pre-conditioning
Individual
susceptibility
16.
17. DIAGNOSIS
Several techniques may be used alone or in combination to
make the diagnosis of no reflow.
Coronary Angiography (Selective Or Subselective).
The Conventional 12 lead ECG.
Myocardial Scintigraphy.
Myocardial Contrast Echocardiography.
Magnetic Resonance Imaging .
Positive Emission Tomography.
Intracoronary Doppler And Pressure Measurements.
Intravascular Ultrasound .
18. CORONARY ANGIOGRAPHY Semiquantitative grading of epicardial antegrade flow according to
the thrombolysis in myocardial infarction (TIMI) flow grades.
TIMI blood flow grades:
Grade 0-refers to no flow at all after the obstruction point.
Grade 1- the contrast material flow beyond the area of obstruction,
but fails to opacify the entire artery.
Grade 2- opacification of the entire artery distal to the occlusion
site , but at a slower rate, than normal.
Grade 3- refers to normal coronary flow.
TIMI flow grade 0 to 2 is predictably assosiated with No-Reflow.
19. Myocardial Blush Grade Describes the relative “blush” or intensity of the
radiopacity of myocardial tissue.
Achieved with an epicardial coronary injection of contrast medium and the
rapidity , that this enhancement clears with. The more intense the myocardial
blush and the faster its clearance, the better the microvascular perfusion.
The MBG is scored on a scale 0-3, with higher score indicating better
perfusion.
MBG 0-1-suggesting of No-Reflow.
MBG 0 to 1 is observed in as high as 50 % of patients with TIMI flow grade
3.
Taken together , angiographic no-reflow can be defined as a TIMI flow grade
< 3 or 3 with MBG 0 or 1.
20.
21. Other angiographic techniques, used for assessing
microvascular integrity in patients with reperfused myocardial
infarction, are the corrected TIMI frame count, defined as the
number of angiographic frames required for the contrast
medium to reach standardised distal landmarks of the coronary
artery,
22. TIMI frame count : the number of angiographic frames
required for the contrast to reach standardized distal landmarks.
LAD: Normal TFC 36 3
LCx: Normal TFC 22 4
RCA: Normal TFC 20 3
23. No-reflow can be assessed during PPCI with Thrombolysis In
Myocardial Infarction (TIMI) flow grade and MBG in the coronary
care unit.
by assessing the ST-segment elevation resolution (STR) after PPCI.
can be better quantified by noninvasive imaging techniques, such as
MCE and contrast-enhanced cardiac magnetic resonance (CMR)
24. ECG
The diagnosis can be suspected with serial 12-lead ECG.
Largely used in clinical arena and trials is measurement of STR
1 hour after PPCI.
With successful thrombolysis ST-segment elevation returns
gradually to baseline.
If there is impaired microvascular perfusion despite successful
thrombolysis, the ST segment elevation persist.
Lack of STR<50 % or 70 %-an established marker of No-
25. Biochemical markers
Serial measures of myoglobin, CK-MB, TNT I,T at
baseline and 60 min after reperfusion is a useful
technique for the assessment of infarct related artery
May reflect the microvascular tissue reperfusion !
26. Myocardial Contrast
Echocardiography A high-energy sonicated microbubbles is injected intravenously
or an intracoronary route and echocardiogram is obtained.
Contrast microbubbles have a rheology similar to that of Red
blood cells.
They freely flow within patent microcirculation safely pass the
pulmonary circulation, and reach intact coronary bed.
Lack of intramyocardial contrast opacification is due to
microvascular obstruction, thus is represents the extent of No-
Reflow
27. MRI
Cardiac magnetic resonance imaging No-Reflow can be diagnosed
as:
Lack of gadolinium enhancement at first pass.
Lack of gadolinium enhancement within a necrotic region, identified
by late gadolinium hyperenhancement.
Hypoenhancement1-2 min after contrast injection is assumed to
represent zones of no-reflow
28. Scintigraphic techniques
Scintigraphic techniques Intracoronary injection of
technitium albumin after successful percutaneous
recanalization demonstrated substantial perfusion
defects.
29. Intracoronary Pressure Measurements.
An adjunctive method which confirms the angiographic
no-reflow phenomenon uses a double-lumen, side-hole catheter to
measure any pressure gradient across the target artery.
The absence of a significant pressure gradient indicates the absence
of mechanical obstruction, thus establishing a key element of
angiographic no-reflow.
30. Intracoronary Doppler flow velocity
changes
Typical Doppler Pattern Of
Angiographic No-reflow:
Early Systolic Retrograde Flow
High Diastolic Deceleration
Rates
Lower Coronary Flow Reserve
31. Techniques for demonstration of no-reflow
Myocardial infarction reperfusion no-reflow
Conventional 12-lead ECG - Persistent ST-segment elevation
Coronary angiography - Suspected if TIMI <3 flow
Dual myocardial scintigraphy - Uptake/perfusion mismatch
Myocardial Tc-99m sestamibi scintigraphy - No-reflow zone
Myocardial contrast echocardiography - No-reflow zone
Nuclear magnetic resonance studies - No-reflow zone
Positron emission tomography - No-reflow zone
Intracoronary Doppler registration - Typical Doppler pattern
34. Prevention and Treatment of
no-reflow
Prevention of no-reflow has to be defined as any
attempt to prevent its occurrence prior to or during the
recanalization procedure.
Treatment of no-reflow defined as any attempt to treat
its occurrence after coronary recanalization.
36. Direct stent implantation, by avoiding balloon-induced
thrombus fragmentation and by entrapping the atherothrombus
under the stent struts, has been suggested as a possible
technique to reduce distal embolization.
37. A more promising technical approach to prevent noreflow
during mechanical reperfusion is the use of thrombectomy
devices and of distal filters.
REMEDIA trial was the first randomized trial to assess the
role of thrombectomy performed with a simple manual
aspiration catheter, as compared with conventional PPCI.
The results of the REMEDIA trial were promising, because
manual thrombectomy was safe and resulted in better
myocardial perfusion indexes as compared with standard
PPCI.
38. Recent trial by Svilaas et al. confirmed the improvement of
reperfusion associated with manual thrombus-aspiration as
compared with standard PPCI.
In the pivotal TAPAS (Thrombosis Aspiration During
Percutaneous Coronary Intervention in Acute Myocardial
Infarction) trial thrombectomy improved tissue perfusion
and reduced cardiac death.
39.
40. Embolic protection devices:
Several randomized trials have studied the role of embolic protection
devices in the treatment of diseased saphenous vein aortocoronary bypass
grafts.
Occlusive protection devices, either distal (Guard- Wire, Medtronic) or
proximal (Proxis, St. Jude Medical) have a theoretical advantage over distal
filter catheters in that they capture vasoactive, proinflammatory and
thrombotic factors that might pass through filter pores and induce
microvascular obstruction
41. In the SAFER (Saphenous Vein Graft Angioplasty Free of Emboli
Randomized Trial) distal embolic protection with a balloon occlusion
and aspiration system (GuardWire) reduced angiographic no-reflow
from 9% to 3% and improved clinical outcome.
In the FIRE trial distal protection with a filter-based catheter was
noninferior to the GuardWire system.
In the PROXIMAL (ProximalProtection During Saphenous Vein
Graft Intervention) trial the efficacy of proximal embolic protection
(Proxis, St.Jude Medical) was noninferior to distal protection
42.
43. Management of ischemia-related
injury
Reducing pain-onset-to balloon time.
Reduce myocardial oxygen consumption and
consequently the severity of ischemia.
The beneficial effects of carvedilol, fosinopril, and valsartan on
coronary no-reflow have indeed been recently demonstrated.
44. Management of reperfusion-related
injury Patients at high risk of No-Reflow on the basis of the presence
of reperfusion-related injury can be treated with drugs like:
Glycoprotein IIb/I11a Antagonists.
Adenosine .
Verapamil
Nicorandil Aimed At Counteracting Endothelial, Platelet,and Neutrophil
Activation.
Selective ET-1 Or TXA 2 Antagonism Might Represent Novel Therapeutic
Aproaches.
45. Adenosine is an endogenous nucleoside mainly produced
by the degradation of adenosine triphosphate, which
antagonizes platelets and neutrophils, reduces calcium
overload and oxygen free radicals and induces
vasodilation.
observational study by Claeys et al. showed that lower
doses of intracoronary adenosine (60 – 90 mcg) were able
to improve STR and reduce infarct size.
46. Adenosine:In small randomized studies, intravenous and distal
intracoronary adenosine administration during primary PCI
achieved superior flow and ventricular function in comparison
to a control group.
AMISTAD-II (Acute Myocardial Infarction Study of
Adenosine-II) trial , which compared intravenous adenosine to
placebo, did not show a clear clinical benefit in the treatment
arm; however, a post hoc analysis suggested a reduction in
mortality and heart failure in patients treated within the first 3
h after onset of evolving anterior Stsegment elevation
myocardial infarction .
47. Verapamil is a calcium-channel blocker that has been
utilized for the prevention of no-reflow.
In a small randomized study by Taniyama et al.23 in
40 patients with first STEMI, intracoronary verapamil
when compared with placebo was associated with
better microvascular function assessed by MCE.
48. Other calcium channel blockers Nicardipine in a dose of 200 µg was
also shown to improve No-Reflow.
Standard dosage: 200 µg.
Contraindications: absolute none. Relative: high-grade arteriovenous
block, severe hypotension, hypersensivity. Main drug interaction:
None.
Main side effects:Brief. Reversible arteriovenous block
49. Glycoprotein IIb/IIIa antagonists results in better epicardial blood flow ,lead to less
No-Reflow phenomenon, leads to the better flow at the level of the microcirculation.
Standard dosage: in adults is 0,25 mg/kg intravenous bolus administered 10-60 min
before the start of the PCI, followed by continuous intravenous infusion.
Neumann and co-workers demonstrated that abciximab improved the
microvascular integrity during stent placement for acute myocardial infarction.
Two updated meta-analyses including the AIDA STEMI results found
no benefit in clinical outcome with intracoronary abciximab
administration, including mortality and reinfarction.
50. Nitroprusside Nitric oxide donor Does not depend on
intracellular metabolism to derive nitric oxide Has potent
vasodilator properties.
Standard dosage: between 50 up to 1000 µg intracoronary.
Contraindications: absolute none. Relative: very severe
hypotension. Main drug interaction: None.
Main side effects: Rare. Hypotonia occurs briefly.
51. Nicorandil Because opening ATP-sensitive potassium channels may be
involved in vasodilatory effect of adenosine, a direct ATP potassium channel
opener nicorandil was attempted in treating of No-Reflow.
Intravenous infusion of nicorandil for 24 hours after PPCI resulted in better
angiographic , functional and clinical outcome.
Standard dosage: 0.5 mg intracoronary plus 4 mg intravenous bolus
Contraindications: Main drug interaction: None. Main side effects:
52. susceptibility to microvascular
injury.
Genetically determined susceptibility to microvascular injury is
difficult to modulate.
Periprocedural reduction of blood glucose was associated with
a reduction of infarct size.
Chronic statin therapy in patients with or without
hypercholesterolemia is associated with lower prevalence of
No-Reflow and better functional recovery
53. Cytoprotection
Activation of intracellular prosurvival pathways has been studied in the setting of
primary PCI.
In 1 study, intravenous nicorandil started before PCI improved myocardial perfusion
and ventricular contraction , aswell as long-term clinical outcome
However, a largerstudy found no reduction in infarct size with nicorandil versus
placebo .
Myocardial post-conditioning afte direct coronary stenting by use of intermittent
low-pressure balloon inflations in the infarct-related artery reduced infarct size and
improved microvascular perfusion as assessedby myocardial blush and long-term
functional recovery
Pharmacological post-conditioning by intravenous administration of cyclosporine, a
direct MPTP blocker, versus placebo, at the time of primary PCI decreased infarct
size
Remote post-conditioning by intermittent inflations of a blood pressure cuff on the
upper limb before reperfusion improved ST-segment resolution following primary
PCI, an effect that was enhanced by administration of morphine
These preliminary studies suggest a beneficial role for conditioning strategies in the
setting of primary infarct PCI.
However, their efficacy in patients undergoing thrombectomy and receiving
glycoprotein IIb/IIIa inhibitors remains
to be defined.
54. Cyclosporine , which block the m-PTP (mitochondrial
permeability transition pore) has been recently shown
to reduce infarct size by 20 % when administrated
intravenously in patients undergoing PPCI.
55. Hyperoxemic reperfusion. Intracoronary hyperoxemic
reperfusionhas been advocated for prevention of reperfusion
injury.Hyperoxemic reperfusion improved microvascular blood
flow and decreased infarct size in a canine model of ischemia
reperfusion .
In the AMIHOT-II (Acute Myocardial Infarction With
Hyperoxemic Therapy II) trial this approach reduced infarct size
but was not associated with improved tissue perfusion as
assessed by ST-segment resolution.
In this trial, only 22% of the patients underwent thrombectomy
and 67% received glycoprotein IIb/IIIa inhibitors.
Because the clinical benefit of hyperoxemic reperfusion has yet
to be shown, the routine use of this invasive strategy in the
current era of routine thrombectomy cannot be recommended at
present.
56.
57.
58. Most recent ESC guidelines indicate adenosine and
verapamil for the treatment of no-reflow.
Intravenous infusion of adenosine at the dosage of 70 μ
g/kg/min over three hours during and after PPCI is
indicated with a class IIb of recommendation and level B of
evidence.
Intracoronary adenosine bolus of 30 – 60 μ g during PPCI
is indicated with a class Iib of recommendation and level C
of evidence.
Intracoronary verapamil bolus of 0.5 – 1 mg during PPCI is
indicated with a class IIb of recommendation and level C of
evidence
