0. The pathogenesis and treatment of no-reflow in patient with ACS
Jian Liu, MD
Chief Physician, Associate Professor of Medicine
Cardiology Department, Peking University People’s Hospital, Beijing

1. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

2. Female, 55 yr.
“ Chest pain 5 months，aggravated for 1 week” .
Risk factors: Hypertension 6 years；Hyperlipidaemia 10 years.
CTA: LAD, RCA severe stenosis and soft plaque.
Diagnosis: Acute coronary syndrome.

3. ECG at rest, pre PCI

4. Left Coronary Artery Angiogram

5. Right Coronary Artery Angiogram

6. After balloon predilation

7. After DES deployed

8. No-reflow
Severe chest pain
Blood pressure dropped
Heart rate dropped

9. Blood flow recover
Nitroglycerin ( IC)
Atropine ( IV )
Dopamine ( IV )

10. Final result

11. ECG 2 days later
Myocardial injury biomarker：TNI 4.62ng/ml

12. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

13. Epidemiology Incidence Influence Overall incidence was 2%;
10%-15% in patients undergoing PCI of SVGs;
30% in AMI undergoing direct PCI;
The hospital mortality and recurrent MI increased 5-10 times;
Associated with increased malignant arrhythmias,cardiac failure and poor
long-term prognosis;
A large area of microvascular injury might impair the healing of the infarct
area and could prevent the delivery of pharmacologic agents into that area;

14. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

15. Definition
No-reflow (NR) was known as "primary percutaneous coronary intervention (PPCI) achieves epicardial coronary artery reperfusion but not myocardial reperfusion";
The term “no-reflow” has been increasingly used in published medical reports to describe microvascular obstruction and reduced myocardial flow after opening an occluded artery;
Manifested as stagnant contrast and myocardial ischemia symptoms.

16. Classification according to the different situation
Experimental no-reflow
Definition
No-reflow induced under experimental conditions
Mechanisms
Myocardial necrosis—stunning
Reperfusion injury—oxygen free radical production
α-adrenergic macro- and microvascular constriction
Local increase in angiotension II receptor density
Neutrophil activation—interaction with endothelium
Myocardial infarction reperfusion no-reflow
No-reflow in the setting of pharmacological and/or mechanical
revascularization for acute myocardial infarction
As for experimental no-reflow
Angiographic no-reflow
No-reflow during percutaneous coronary interventions
Distal embolization of plaque and/or thrombus
Local release of vasoconstrictor substances

17. Classification according to morphological and functional studies
Structural no-reflow
- microvessels confined within necrotic myocardium exhibit irreversible damage of the cellular components of their wall.
Functional no-reflow
- patency of anatomically intact microvessels is compromised because of spasm and/or microembolisation.

18. Classification according to the duration of the preceding myocardial ischemia
Reperfusion NR
Ischemia-reperfusion injury
Myocardial edema
Endothelial swelling
Capillary obstruction
Vasospasm
Inflammatory response
Distal coronary embclization
Interventional NR
Distal coronary embolization
- Microvascular obstruction
- Inflammatory response
- Secondary
Duration
of Preceding
ischemia
seconds-minutes
hours
Circulation. 2008;117:

19. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

20. Pathophysiology Mechanical obstruction from embolization
Vascular autoregulation
Extrinsic coagulation pathway
Leukocyte adherence, platelet thrombi, and free radicals
Microvascular ischemia and edema
Vasoconstrictor mediators
Individual susceptibility

21. Coronary microembolization
Plaque rupture/fissure
Debris Thrombotic material Soluble factors
Microembolization
Acute ischemia
Protection
Infarctlets
TNFα
Inflammatory reaction
Serotonin
TXA2
Adhesin
NO, TNF, ROS
Arrhythmia
Myocardial dysfunction
Coronary reserve

22. Vascular autoregulation
Atherosclerotic coronary arteries present vascular dysfunction manifesting as α-adrenergic over-activation and vasoconstriction;
Coronary vasodilator response and then in left ventricular ejection fraction improved after long-term administration of oral α-adrenergic blockers post PCI.

23. Extrinsic coagulation pathway
Many studies support the central role of the tissue factor (TF) and factor VII to contribute to inflammation and injury in myocardial ischemia-reperfusion;
TF is exposed in leukocytes, platelets, and endothelial cells after local vascular trauma leading to thrombosis.

24. Leukocyte adherence, platelet thrombi and free radicals
Leukocytes and their activation, the accumulation of neutrophils in the reperfused area, and the production of reactive oxygen species play a pivotal role in the pathogenesis of myocardial injury and contribute to no-reflow.

25. Microvascular ischemia and edema
After a prolonged ischemia (90 minutes), a series of microvascular changes occur, particularly capillary damage with edema;
This mechanism represents the ‘‘structural’’ or ‘‘anatomical’’ no-reflow that is very difficult to treat;
The only rescue system may be to open the IRA in the shortest time possible.

26. Vasoconstrictor mediators
Endothelial dysfunction induces a dysregulation in the balance between vasodilators and vasoconstrictors,in favor of the latter;
Inappropriate vasoconstriction is likely to be an important mechanism of no-reflow.

27. Individual susceptibility
Diabetes has been associated with impaired microvascular reperfusion after PCI;
Hypercholesterolemia induces high endothelial oxidative stress, thus aggravating reperfusion injury in animal models.

28. Summarizing different mechanisms
Heart 2002; 87: 162–8

29. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

30. Influencing factors of NR
The course of ACS and reperfusion time
Characteristics of coronary artery lesions
Pathological vessels and interventions
Acute phase of ACS (<2w)
Reperfusion time<6h
Plaque rupture
Ulcerative lesions
Rich lipid,etc
SVG
Rotational atherectomy

31. Evaluation methods Diagnostic technique Parameter evaluated
Definition of no-reflow
Coronary angiography
TIMI flow grade
TIMI flow grade <3
MBG
MBG <2
TIMI and MBG
TIMI flow grade ≤3 with MBG <2
ECG
STR
STR <50%
Myocardial contrast
echocardiography
Intramyocardial contrast
opacification
Segmental lack of
contrast opacification
Cardiac magnetic resonance
Myocardial enhancement
by gadolinium
Lack of gadolinium enhancement during first pass or within a
ecrotic region identified by gadolinium hyperenhancement
Single-photon emission
tomography and PET
Myocardial perfusion
tracer captation
Lack of perfusion tracer captation

32. Coronary angiography No-reflow Reflow
The sensitivity of TIMI flow grade is rather low as no-reflow occurs even in patients showing TIMI flow grade 3.
MBG provides a semi-quantitative evaluation of tissue perfusion after injection of contrast media in the epicardial vessel,represents a newer and more sensitive method.

33. ECG
Reflow
No-reflow
Electrocardiographic STR is assessed 1 h after PCI,represents the most widely used technique, both in experimental studies and in clinical practice.
Sustained elevation of the ST segment after successful PCI is also associated with unfavorable functional and clinical outcomes.
Almost 30% of patients with TIMI flow grade 3 and MBG 2 or 3 do not exibit STR.

34. Myocardial contrast echocardiography
Reflow
No-reflow
MCE uses ultrasound to detect the presence of microbubbles in myocardial microvessels;
Microvascular obstruction is detectable as a perfusion defect during myocardial contrast
echocardiography and represents the extent of no-reflow;
AMICI study indicated the extent of no-reflow was the best predictor of adverse left ventricular remodeling after STEMI, being superior to STR and MBG among patients with a TIMI flow grade 3.

35. Cardiac magnetic resonance
Reflow
No-reflow
No-reflow can be diagnosed as a lack of
gadolinium enhancement during first pass
or a lack of gadolinium enhancement
within a necrotic region, identified by late
gadolinium hyperenhancement;
CMR evaluation of microvascular perfusion
has been shown to strictly correlate with
MBG;
The detection of hypoenhancement zones
on first-pass perfusion CMR,is associated
with permanent dysfunction at follow-up

36. New methods of assessing no-flow
Diastolic deceleration time(DDT)
1. Assessed by noninvasive transtoracic Doppler echocardiography,
strictly predicts LV dilation at 6 months ;
2. DDT less than 600 ms 7 days after AMI was an independentpredictor
of LV remodeling and microvascular dysfunction.
Index of microvascular resistance
1. A new invasively assessed measure of microvasculature function
using a pressure sensor/thermistor-tipped guidewire during PCI;
2. The value of the index of microvascular resistance greater than 32 U
has been shown to strictly correlate with wall motion score at 3 months
better than other angiographic measures of microvascular dysfunction.

37. Contents 1 Case report 2 Epidemiology of no reflow 3
Definition and classification 4
Pathophysiology of no reflow 5
Influencing factors and diagnostic methods 6
Prevention and treatment of no reflow

38. Prevention and treatment of no reflow
Medical therapy
Anti-platelet therapy: Abciximab
Vasodilators: Nitroglycerine, Adenosine, Calcium channel
blockers, Nicorandil,Sodium nitroprusside
Intracoronary thrombolytics: Streptokinase
New drugs: Cyclosporine,Statins,Endothelin-1 and
Thromboxane-A2 receptor antagonists

39. Evidence Concerning Medical Prevention and Treatment of No-Reflow
Drug
Evaluated
Study
Patients (n)
Timing of
Intervention
Primary End Points
Results
Abciximab
Thiele
et al
154
Periprocedural
Infarct size and extent of microvascular obstruction
Significant reduction in infarct size and microvascular obstruction with intracoronary abciximab
Adenosine
Marzilli 54
Pre-PCI
Feasibility, safety, and TIMI flow
Safe and feasible in MI, reduction in
incidence of no-reflow, and improvement of LVEF
Ross
2118
Pre- and
post-PCI
Inhospital heart failure, rehospitalization for heart failure, or 6-month death.
No effect on clinical outcomes and infarct size reduction with adenosine 70 mg/kg per min
Nitroprusside
Amit 98
During PCI
Corrected TIMI frame count and ST resolution >70%
No effect on coronary flow and myocardial
tissue reperfusion, improvement in
clinical outcomes at 6 months
Nicorandil
Ishii
360
Cardiovascular death or
rehospedalization for
congestive heart failure.
Improved myocardial reperfusion, fewer
deaths, and less cardiac failure after 2.4-
year follow-up
Verapamil
Piana 39
Corrected TIMI frame count, TIMI flow grade, and ST resolution.
Improvement in TIMI flow grade, reduction
in cineframes to opacify a distal vascular
landmark, and relief of chest pain and
ischemic ST-segment shifts
Cyclosporine
Piot 58
Infarct size
Smaller infarct size but no effect on final
TIMI flow
Statins
Iwakura
293
Incidence of no-reflow and EF
Lower incidence of no-reflow, better wall motion, smaller LV dimension, and better EF

40. Distal or proximal protection
Distal occlusion
Distal filters
Proximal occlusion/
flow reversal
Circulation 2006; 113: 2651–6.

41. Prevention and treatment of no reflow
Mechanical therapies
Embolic protection devices
1. Distal or proximal protection
2. Thrombectomy devices
PCI techniques :
1. Minimization of balloon inflations
2. Stent deployment without predilation
3. Pre- and postconditioning methods

42. Thrombectomy devices Manual thrombectomy devices
1. Export [Medtronic Corporation, Minneapolis,MN, USA]
2. Driver CE [Invatec, Brescia, Italy]
3. Pronto [Vascular solutions, Minneapolis, MN, USA]
Mechanical thrombectomy devices
1. Angiojet [MEDRAD Interventional/Possis Medical Inc., Minneapolis,MN, USA]
2. X-Sizer [eV3, White Bear Lake, MN,USA]

43. Manual thrombectomy devices
a. The Diver CE device.b. The Pronto catheter. c. The Export catheter. d. The Hunter catheter. e. The VMax catheter.

44. Mechanical thrombectomy devices
The Angiojet System
The Rinspirator system
The X-sizer system

45. Angiographic Exclusion
Effect of Thrombectomy Devices on Surrogate End Points of Myocardial Reperfusion
Study
Thrombectomy
Device
Patients (n)
Angiographic Exclusion
Criteria
GP IIb/IIIa Use (%)
Primary
End Points
Results
Noel et al
Export 50
TIMI flow > 2
N/A
STR > 70%
50% vs 12%
EXPORT
249
RVD < 2.5 mm TIMI flow 2-3
67.8
STR > 50% þ MBG 3
85% vs 71.9%
EXPIRA
175
TTG < 3
100
MBG 3 STR > 70%
70.3% vs 28.7%
TAPAS
1071
None
93.4
MBG 0 or 1
17.1% vs 26.3%
Lipiecki
et al 44 55
Infarct size
30.6% vs 28.5%
Liistro
111
71% vs 39%
Chao 74 26
△DTIMI flow △MBG
2.2 vs vs 1.0
Antoniucci
Angiojet
RVD < 2.5 mm 98
Early STR 50%
90% vs 72%
AiMI
480
RVD < 2.0 mm
94.5
12.5% vs 9.8%
JETSTENT
501
TTG < 3 RVD < 2.5 mm
97.5
85.8% vs 78.8% 11.8% vs
12.7%

46. Both manual and mechanical were associated with better STR, albeit manual thrombectomy demonstrated a clear superiority.Manual thrombectomy device suggest that it is associated with a benefit in terms of death, stroke, and MI compared to standard PCI.Mechanical thrombectomy, on the other hand, does not seem to improve outcome over standard PCI.
Therefore, current evidence suggests the routine use of manual thrombectomy in primary PCI
Costopoulos C, Gorog DA, Di Mario C, Kukreja N. Use of thrombectomy devices in primary percutaneous coronary intervention: a systematic review and meta-analysis [published online December 11, 2011]. Int J Cardiol

47. Prevention and treatment of no reflow
Mechanical therapies
Embolic protection devices
1. Distal or proximal protection
2. Thrombectomy devices
PCI techniques :
1. Minimization of balloon inflations
2. Stent deployment without predilation
3. Pre- and postconditioning methods

48. Minimize distal embolization: MGuard stent (MGS, Inspire-MD, Tel-Aviv, Israel)
A bare-metal stent with a polyethylene theraphthalate mesh coverage anchored to the external surface of the struts,rationale is to minimize distal embolization during PCI;
The first multicenter clinical experience of MGS deployment in STEMI setting showed that all angiographic procedures were successful with high coronary and myocardial perfusion grades, and a high rate of complete STR (90%). After hospital discharge, no adverse cardiac eventswere found up to 30-day follow-up.
European guidelines : mesh-covered stents may be considered
for PCI of highly thrombotic or vein graft lesions(Class IIb,Level C)

49. Prevention and treatment of no reflow
Others
Oxygen intracoronary administration
Therapeutic hypothermia

50. Future perspectives
The angiopoietin-like protein 4 (ANGPTL4) : a recent study suggested that ANGPTL4 might modulate vascular damage and infarct size during MI, thus constituting a relevant target for therapy.
The intracellular inflammatory mediator nuclear factor-kappaB (NF-kB): in animal study, NF-kB significantly attenuated neutrophil infiltration in the no-reflow area as well as the expansion of no-reflow,and reduced the levels of tumor necrosis factor-a, intercellular adhesion molecule 1, and ligand 16, also known to be important mediators of the inflammatory response at plaque level

51. Thank you for your attention ！