The Detrimental Impact of Chronic Renal Insufficiency

1
The pathogenesis and treatment of no-reflow in
patient with ACS
Jian Liu, MD Chief Physician, Associate
Professor of Medicine Cardiology Department,
Peking University Peoples Hospital, Beijing
2
Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
3

• Female, 55 yr.
• Chest pain 5 months,aggravated for 1 week .
• Risk factors Hypertension 6 yearsHyperlipidaem
  ia 10 years.
• CTA LAD, RCA severe stenosis and soft plaque.
• Diagnosis Acute coronary syndrome.

4
ECG at rest, pre PCI
5
Left Coronary Artery Angiogram
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Right Coronary Artery Angiogram
7
After balloon predilation
8
After DES deployed
9
No-reflow

• Severe chest pain
• Blood pressure dropped
• Heart rate dropped

10
Blood flow recover

• Nitroglycerin ( IC)
• Atropine ( IV )
• Dopamine ( IV )

11
Final result
12
ECG 2 days later

• Myocardial injury biomarkerTNI 4.62ng/ml

13
Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
14
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

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Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
16
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.

17
Classification according to the different
situation
Experimental no-reflow Experimental no-reflow
Definition No-reflow induced under experimental conditions
Mechanisms Myocardial necrosisstunning Reperfusion injuryoxygen free radical production a-adrenergic macro- and microvascular constriction Local increase in angiotension II receptor density Neutrophil activationinteraction with endothelium
Myocardial infarction reperfusion no-reflow Myocardial infarction reperfusion no-reflow
Definition No-reflow in the setting of pharmacological and/or mechanical revascularization for acute myocardial infarction
Mechanisms As for experimental no-reflow
Angiographic no-reflow Angiographic no-reflow
Definition No-reflow during percutaneous coronary interventions
Mechanisms Distal embolization of plaque and/or thrombus Local release of vasoconstrictor substances
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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.

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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. 20081173152-3156
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Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
21
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

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Coronary microembolization
Debris Thrombotic material
Soluble factors
Plaque rupture/fissure
Microembolization
Acute ischemia
Protection
Infarctlets
TNFa
Inflammatory reaction
Serotonin TXA2
Adhesin
NO, TNF, ROS
Arrhythmia
Myocardial dysfunction
Coronary reserve
23
Vascular autoregulation

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

24
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.

25
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.

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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.

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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.

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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.

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Summarizing different mechanisms
Heart 2002 87 1628
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Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
31
Influencing factors of NR

• The course of ACS and reperfusion time
• Characteristics of coronary artery lesions
• Pathological vessels and interventions

• Acute phase of ACS (lt2w)
• Reperfusion timelt6h

• Plaque rupture
• Ulcerative lesions
• Rich lipid,etc

• SVG
• Rotational atherectomy

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Evaluation methods
Diagnostic technique Parameter evaluated Definition of no-reflow
Coronary angiography TIMI flow grade TIMI flow grade lt3
Coronary angiography MBG MBG lt2
Coronary angiography TIMI and MBG TIMI flow grade 3 with MBG lt2
ECG STR STR lt50
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
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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.

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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.

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Myocardial contrast echocardiography
No-reflow
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.

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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

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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-tip
  ped 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.

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Contents
Case report
1
Epidemiology of no reflow
2
Definition and classification
3
Pathophysiology of no reflow
4
Influencing factors and diagnostic methods
5
Prevention and treatment of no reflow
6
39
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

40
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 et al 54 Pre-PCI Feasibility, safety, and TIMI flow Safe and feasible in MI, reduction in incidence of no-reflow, and improvement of LVEF
Adenosine Ross et al 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 et al 98 During PCI Corrected TIMI frame count and ST resolution gt70 No effect on coronary flow and myocardial tissue reperfusion, improvement in clinical outcomes at 6 months
Nicorandil Ishii et al 360 Pre-PCI 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 et al 39 During PCI 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 et al 58 Pre-PCI Infarct size Smaller infarct size but no effect on final TIMI flow
Statins Iwakura et al 293 Pre-PCI Incidence of no-reflow and EF Lower incidence of no-reflow, better wall motion, smaller LV dimension, and better EF
41
Distal or proximal protection
Distal occlusion
Distal filters
Proximal occlusion/ flow reversal
Circulation 2006 113 26516.
42
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

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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

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Manual thrombectomy devices
a. The Diver CE device.b. The Pronto catheter. c.
The Export catheter. d. The Hunter catheter. e.
The VMax catheter.
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Mechanical thrombectomy devices
The Rinspirator system
The Angiojet System
The X-sizer system
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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 gt 2 N/A STR gt 70 50 vs 12
EXPORT Export 249 RVD lt 2.5 mm TIMI flow 2-3 67.8 STR gt 50 þ MBG 3 85 vs 71.9
EXPIRA Export 249 RVD lt 2.5 mm TIMI flow 2-3 67.8 STR gt 50 þ MBG 3 85 vs 71.9
EXPIRA Export 175 RVD lt 2.5 mm TIMI flow 2-3 TTG lt 3 100 MBG 3 STR gt 70 70.3 vs 28.7
TAPAS Export 1071 None 93.4 MBG 0 or 1 17.1 vs 26.3
Lipiecki et al Export 44 None 55 Infarct size 30.6 vs 28.5
Liistro et al Export 111 None 100 STR gt 70 71 vs 39
Chao et al Export 74 None 26 ?DTIMI flow ?MBG 2.2 vs 1.5 2.3 vs 1.0
Antoniucci et al Angiojet 100 RVD lt 2.5 mm 98 Early STR 50 90 vs 72
AiMI Angiojet 480 RVD lt 2.0 mm 94.5 Infarct size 12.5 vs 9.8
JETSTENT Angiojet 501 TTG lt 3 RVD lt 2.5 mm 97.5 Early STR 50 Infarct size 85.8 vs 78.8 11.8 vs 12.7
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Therefore, current evidence suggests the routine
use of manual thrombectomy in primary PCI

• 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.

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. 2011.
48
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

49
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)
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Prevention and treatment of no reflow

• Others

• Oxygen intracoronary administration
• Therapeutic hypothermia

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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

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• Thank you for your attention !