腦血管疾病之機轉

腦中風• 缺血性中風 (65-85%)

– 腦梗塞因腦血管硬化狹窄或因血凝塊流至腦血管造成腦血管閉塞所導致

– 暫時性腦缺血發作 (TIA)

• 出血性中風 – 腦出血 (15-25%)

– 蜘蛛網膜下出血 (SAH) (3-8%)

• 其它顱內出血 : 依出血部位區分 , 一般與外傷有關 , 不歸類於一般之腦中風

95 年十大死因• 排名與上年相同，其死亡人數占率依序為：

– (1) 惡性腫瘤占 28.1%– (2) 腦血管疾病占 9.3%– (3) 心臟疾病占 9.1%– (4) 糖尿病占 7.2%– (5) 事故傷害占 5.9%– (6) 肺炎占 4.0%– (7) 慢性肝病及肝硬化占 3.7%– (8) 腎炎占 3.5%– (9) 自殺占 3.3%– (10) 高血壓性疾病占 1.3%

• 慢性肝病及肝硬化、糖尿病、肺炎降幅最為明顯，分別下降 12 8%‧ 、 11 4%‧ 及 10 1%‧ ，惟自殺微增 1 1% ‧

Primary prevention

Acute stroke treatmentThrombolysis

Antiplatelet agentsAcute stroke care

Risk factors surveyCarotid intervention

Long-term treatment

Antithrombotic agentsRisk stratification &

Modification of risk factorsStem cell transplant

5-15% annual risk of stroke recurrence

Hemeostatsis and Coagulation

Vascular-bed Specific Homeostasis

Vascular-bed Specific Homeostasis

Physiologic Response to Vessel Injury

VESSEL DAMAGE

initiates

PLATELETACTIVATION

COAGULATION

Plateletplug

forms

Platelet surfacebecomes

Available for coagulation

activities

Platelet-fibrinclot

Collagenexposure

Tissue factorexposure

IntrinsicPathway

Extrinsic Pathway

Fibrin clot

Thrombosis? Embolism?Thromboembolism !!!

STROKE

15%

85%

Hemorrhage

Ischemic Stroke

20% 25%

Large Artery

Lacunae

Embolism

Cryptogenic

Unusual

Heterogeneity of PathogenesisMCA penetrating artery i

nfarct (lacunae) Lipohylinosis, microane

urysm Microatheroma In situ thrombosis Artery to artery embolis

m Low flow infarct Cardiac emboli

MCA main trunk infarct In situ thrombosis Artery to artery

embolism Low flow infarct Cardiac emboli

Large artery disease Lacunae

20% 30% 5%

Stroke subtype

Infarct size vs. arterial lesion

Emboli Monitoring• Cerebral emboli are often the cause of TIA and st

roke.• Embolic material can be seen, and counted by the

Doppler ultrasound. • The detection of emboli can further the understan

ding of the mechanism of stroke, guide therapies and identify patients at increased risk.

• Emboli that break off at remote sites and float downstream causing symptoms and brain infarction. Monitoring for emboli is also done during cardiopulmonary bypass, cerebral angiography and carotid endarterectomy.

• OR for stroke or peripheral embolism in patients with severe arch atheroma >4, and for mobile atheroma > 12

** severe atheroma: > 4mm, ulcerated, or mobile

Ischemic Penumbra

• Tissue surrounding the core region of infarction is ischemic but reversibly dysfunctional and is referred to as the ischemic penumbra.

• The penumbra may be imaged by using perfusion-diffusion imaging with MRI.

• The ischemic penumbra will eventually infarct if no change in flow occurs, and hence saving the ischemic penumbra is the goal of thrombolytic therapy and newer therapies under investigation.

Brain Attack: time is brain

• Rapid evaluation of patients is essential for use of time-sensitive treatments such as thrombolysis.

• Call emergency medical services immediately if they experience the sudden onset of any of the following– loss of sensory and/or motor function on one sid

e of the body (nearly 85% of ischemic stroke patients have hemiparesis)

– change in vision, gait, or ability to speak or understand

– a sudden, severe headache.

                                                                                                                                                                                                                                                                                                       

         

Factors influencing cerebral ischemic injury

• Rate of onset and duration of ischemia• Collateral circulation• Cerebral autoregulation• Health of systemic circulation• Hematological factors• Temperature• Glucose metabolism

側枝循環自我保護

Cerebral autoregulatory responses

Simplified Diagram of Mechanisms of Cerebrovascular Regulation

Cerebrovascular autoregulation and risk of stroke

Transcranial Doppler Ultrasound

High Resolution for dynamic change; Non-invasive; Safe; Continuous long-term monitoring

Baseline 6cycle

Valsavamaneuver

HV 7%CO2

VMRBaseline

TiltS/P NTG

Tilt

Baseline

10 mins 5 mins 10 mins 10 mins 15 mins 15 mins

6 cycle VM VMR Baseline tilt S/P NTG tilt

Evidence of Critical Closing Pressure (CrCP) in Cerebral Circulation: TCD in Brain Death

Supine After Head-Up Tilt

Stroke 1994;25:2407

6 of 12 patients with orthostatic hypotension demonstrated reverse flow during diastolic phase in 70° upright position.

Guideline or Consensus Statement Management Recommendation for Primary

Prevention of Ischemic Stroke (AHA, Circulation, 2001)

•Nonmodifiable risk factors

• Well-documented Modifiable Risk factors

• Less Well-documented or potentially modifiable risk factors

Nonmodifiable Risk Factors

Factor Incidence

Age Doubling each 10 years after age 55

Race Blacks 233/100,000

Hispanics 196/100,000

White 93/100,000

Sex man 174/100,000

woman 122/100,000

Family Hx of Stroke /TIA RR paternal Hx:2.4

RR maternal Hx:1.4

Well-documented Modifiable Risk Factors

Factors Relative Risk

Hypertension 50 y 4.0

60 y 3.0

70 y 2.0

80 y 1.4

Smoking 1.8

Diabetes 1.8-6

Asymptomatic carotid stenosis 2.0

Sickle cell disease 200-400

Hyperlipidemia 1.8 (TC 240-279),2.6 (TC> 280mg/dl)

Atrial fibrillation 50-59y 4.0

60-69y 2.6

70-79y 3.3

80-89y 4.5

Less Well-documented or Potentially Modifiable Risk Factors

Factor Relative risk or OR

Obesity 1.75-2.37

Physical inactivity 2.7

Alcohol abuse

>=5 drinks/d 1.6

not moderte 1.8

Hyperhomocycteinemia 1.3-2.3

Drugs abuse ?

Hypercoagulability 0.8-8.3

Hormone replacement 0.23-1.46

Oral contraceptivs 0.6-7.09

Inflammatory processes ….

NINDS rt-PA Study:Part 2 Primary Outcome (3 mos)

0

10

20

30

40

50

60

NIHSS Barthel Rankin Glasgow

tPA

placebo

% p

atie

nts

wit

h li

ttle

or

no d

isab

ilit

y

Global comparison of all scales combined (Wald test), p<0.01

31%

20%

26%

39%38%

50%

32%

44%

NEJM 1995; 333:1581-1587

• IV rtPA (0.9 mg/kg) given within 3 hours of stroke onset increased the likelihood of recovery at 90 days compared to placebo

• Hemorrhage rate 6.4% vs. 0.6% placebo, but no significant difference in mortality

• All subgroups had better outcome when treated with tPA compared to placebo

• Benefits of tPA persisted to one year

NINDS rt-PA Study:Summary

NINDS rt-PA Study: Hemorrhage

• 22 symptomatic ICHs• Only 2 were in the pla

cebo group• Any subgroups more p

rone to ICH after treatment with tPA?

NINDS rt-PA Study:Part 1 Primary Outcome (24 hrs)

0

10

20

30

40

50

60

70

placebo tPA

NS

% p

atie

nts

≥4 p

tim

prov

emen

t in

NIH

SS

39%

47%

NEJM 1995; 333:1581-1587

Intra-arterial Thrombolysis

Occluded artery Flow Restored by IA tPA

Intuitive appeal: 1. Local delivery 2. Fewer bleeding complications 3. Thrombolysis until recanalization

Other studies on thrombolysis

• Negative thrombolysis studies– The European Cooperative Acute Stroke Study (ECASS) I:

used a higher dose of rtPA (1.2 mg/kg)– ECASS-II: used the NINDS dose of rtPA (0.9 mg/kg; maxim

um dose, 90 mg) but allowed up to the sixth hour– ATLANTIS: 0.9mg/kg, Max 90mg between 3 and 5 h– No significant benefit was found, but improvement was foun

d in post hoc analyses. • Three trials using streptokinase reported increased mortality for

patients receiving streptokinase.• Early administration of the fibrinolytic agent ancrod appears to i

mprove outcomes

Summary

• IV tPA given within 3 hrs of stroke onset reduces disability at 90 days compared to placebo. Level I evidence

• IV streptokinase (1.5 MU IV) increases the risk of hemorrhage and death. Level I evidence

• IA r-ProUK given within 6 hrs of stroke onset reduces disability at 90 days, but the drug is not available (not FDA-approved). Level I evidence

• There only Level IV or V evidence to support the use of IA thrombolysis in acute vertebrobasilar occlusive disease

Pathogenesis of cerebral atherosclerosis

Atherosclerosis TimelineAtherosclerosis Timeline

FoamFoamCells Cells

FattyFattyStreak Streak

IntermediateIntermediateLesion Lesion AtheromaAtheroma

FibrousFibrousPlaquePlaque

ComplicatedComplicatedLesion/Lesion/RuptureRupture

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

From FirstDecade

From ThirdDecade

From FourthDecade

Endothelial DysfunctionEndothelial Dysfunction

Mean IMT Std Dev Success 1.79 mm 0.18 mm 96%

Mean IMT Std Dev Success 0.70 mm 0.07 mm 99%

Automatic Calculation of Intima-Media Thickness

Heterogeneous PlaqueFatty core or intraplaque hemorrhage

CCA

ICA Total Occlusion: Acute vs. Chronic

Acute thrombosis with anechoic plaque and clear intima margin

Heterogenous, shadowing plaque (chronic fibrocalcified plaque)

Acoustic shadow

LumenFibrous Cap

Lipid Core

Lipid Core

Fibrous Cap

Lumen

Vulnerable Plaque

Stable Plaque

• Thick fibrous cap• Smooth muscle cells: more extracellular matrix• Lipid-poor plaque

• Thin fibrous cap• Inflammatory cell infiltrates: proteolytic activity• Lipid-rich plaque

Libby P. Circulation. 1995;91:2844-2850.

Vulnerable vs Stable Atherosclerotic Plaques

Inflammatory Markers and Novel Risk Factors

• IL-6, ICAM, MIC-1, CD40 ligand: inappropriate for routine clinical use, or short half-life for clinical evaluation

• Fibrinogen: a biomarker for both inflammation and thrombosis, poorly standarized

• WBC count, ESR: unreliable in clinical settings• Lipoprotein(a) and homocysteine: useful for patin

ets with markedly premature and unexplained atherosclerosis, not for population-based study

C-reactive Protein for Global Cardiovascular Risk Prediction

• Predict incident MI, stroke, PAD, and sudden cardiac death• Predict risk of recurrent ischemia or death in patients with stable

or unstable angina• A stronger predictor of cardiovascular events than LDL

cholesterol (NEJM, 2002:347:1557)

• Add prognostic information at all levels of calculated Framingham Risk and at all levels of the metabolic syndrome

• Simple and inexpensive method to improve global risk prediction and compliance with preventive approaches.

Normal Endothelial Function

• Vasomotion regulation

• Inhibition of platelet aggregation and thrombus formation

• Maintenance of relative impermeability

Endothelial Dysfunction to CVD

Endothelial Vasodilatory Function

Inflation of pneumatic cuff higher than systolic BP around forearm or upper arm

Measure baseline diameter of brachial artery

Deflation of cuff 5 min later

Measure the diameter changes in brachial artery; usually maximum at 1 min

Methods to Assess Endothelial Function

• Invasive Measures:– Intra-arterial infusion of specific as Ach, substance P, bradyk

inin; Quantitative Coronary angiography: Coronary Dilation via Acetylcholine Response

– Increased shear stress by cardiac pacing, exercise, cold-presser testing

• Noninvasive Measures: Flow-mediated dilation– Brachial ultrasound (FMD), best-validated technique– With forearm plethysmography

• Determination of soluble endothelial markers– ET-1, vWF, t-PA, PAI-1, ICAMs, VCAMs, E-selectin, P-sel

ectin, asymmetric dimethylarginine, thrombomodulin adhesion molecules, N-oxides

Clinical Significance of FMD

• Brachial FMD predict future cardiovascular diseases (Am J Cardiol 1998, 82:1535; Am Heart J 1999, 138:731;

JACC 1995, 26:1235) and postoperative occurrence of cardiovascular events (Circulation 220, 105:1567).

• Useful in judging the potential utility of new interventions for cardiovascular diseases

• Useful to assess long-term cardiovascular risk in a low risk population

Inflammatory Modulators Produced by Platelets

1. Libby P, Simon DI. Circulation 2001; 103: 1718–20. 2. von Hundelshausen P et al. Circulation 2001; 103: 1772–7. 3. Wever RMF et al. Circulation 1998; 97: 108–12. 4. Hermann A et al. Platelets 2001; 12: 74–82. 5. Robbie L, Libby P. Ann N Y Acad Sci 2001; 947: 167–79.

Transforming growthfactor-ß5

• Stimulate smooth muscle cell biosynthesis

Nitric oxide3

• Effects on monocyte, leucocyte, endothelium, and smooth muscle cells

CD154 (CD40 ligand)1,4

• Regulates macrophage and smooth muscle cell functions

RANTES2

• Influences macrophage adhesion to endothelial cell

Platelet-factor 41

• Mediates shear-resistant arrest of monocytes to endothelium

PLATELET

Platelet-derived growthfactor (PDGF)1 • Induces proliferation of

smooth muscle cells

Thrombospondin1

• Interacts with cell surface receptors

ThrombinSerotoninEpinephrineCollagen

ADPADP

Activation

TXATXA22

ActivatedPlatelet

COXCOX

AspirinGp Gp IIb/IIIa fibrinogenfibrinogenreceptorreceptor

To neighboringTo neighboringplateletplatelet

Clopidogrel

Ticlopidine

Platelet agonistsADPATPserotonincalciummagnesium

Degranulation

Adhesive proteins

thrombospondinfibrinogenp-selectinvWF

Coagulation factors

factor Vfactor XIPAI-1

Inflammatory factors

platelet factor 4CD 154 (CD 40 ligand)PDGF

IV Gp IIb/IIIaInhibitors

TXA, thromboxane; PDGF, platelet-derived growth factor.

Aggrenox: Benefits Beyond Platelet Inhibition

Platelet inhibition/thrombinreceptor reduction

Eisert WG. in Platelets (Academic Press) 2002: 803-815; Aktas B. Stroke. 2003; 34: 764-769. Eisert WG. Am J Therapeutics. 2001; 8: 443-449; Biaggioni I. J Investig Med. 2003; 51: S370.

Malinin A. HeartDrug 2002; 2: 93-104; Weyrich AS. et al. P134. ESC 2003.

• Additive to NO increase

• Anti-inflammatory

• Antioxidant

• Cell membrane protection

• Antiproliferative

• Tissue preconditioning

Additional effects atthe vessel wall:

Antithromboticproperties

MCP-1

Neuroprotection in cerebral ischemia: facts and fancies

FACTS:Many neuroprotective agents have proven efficacious in animal models, but so far no human study has shown a statistically significant benefit in patients with acute ischaemic stroke on primary endpoint measures.

FANCIES: A drug with almost no adverse effects could be given by ambulance staff on the way to hospital and induce a clinically significant effect on outcome. Since there were only benefits and no risks, diagnostic skills by neurologists and neuroradiological evaluations would no longer be required.

Neuroprotective agents

• Neurotrophic: Basic-EGF and Gangliosides

• Ca channel blocker: Nimodipine and Flunarizine

• NMDA receptor antagonists: Aptiganel and YM-90K

• Lubeluzole• Glutamate antagonist: Selfotel• GABA agonist: clomethiazole• Glycine site antagonists: Gavestinel• Citicoline• Inhibitor of lipid peroxidation: Tirilazad

mesylate• Murine monoclonal antibody to human I

CAM-1: Enlimomab

• No agent with putative neuroprotective effects can be recommended for the treatment of patients with acute ischemic stroke at this time (grade A). No such agents are available for clinical use.

Why have neuroprotective agents failed in human stroke trial ?

• The effects of neuroprotective agents are time dependent, and treatment has often been initiated much later than in successful experimental stroke models.

• Insuffucuent doses of the drugs and slow availability of the drug at the target area.

• Future approaches: – In animal study: candidates should be standardized; using older anim

als with common co-morbidity such as atherosclerosis; discovering highly effective new neuroprotective agents; trials of combination therapies.

– In clinical trial: treatments should be initiated early; neuroprotective agents, possibly combinations of agents, involving several of cell damage mechanisms; neuroprotective agents shown to be highly effective in stroke models; highly selected patients

Specific patient group: V/Q mis-match

The immunosuppressant FK506 (tacrolimus) exerts variable neuroprotection following focal ischemia in animals.FK506 significantly protected the ischemic brain only in the mismatch cortex where the initial apparent diffusion coefficient (ADC) was normal and there was a mild reduction of cerebral blood flow (CBF). --Magn Reson Med. 2004 Jun;51(6):1173-

Cellular effects of oxygen radicals

• Lipid peroxidation• Protein denaturation• Inactivation of enzymes• Nucleic acid and DNA damage• Release of Ca++ from intracellular stores• Damage to cytoskeleton• Chemotaxis• Signaling pathways in the pathogenesis of apoptot

ic cell death

Cerebral vascular effects of oxygen radicals

• Vasodilation• Alternation in reactivity to CO2 and endothelium-

dependent vasodilators• Increased platelet aggregability• Increased endothelial permeability• Focal destructive lesions of endothelial cell membr

anes

Generation of oxygen radicals and clearance pathways (1)

• Results from pharmacological trials and studies using Tg/KO rodents provide strong evidence to support the importance of SODs and superoxide in the pathophysiology of ischemic brain injury

• Reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. Mitochondria produce superoxide anion radicals and hydrogen peroxide (H2O2) under normal physiological conditions.

• Reperfusion after ischemia causes overproduction of reactive oxygen species (ROS) in mitochondria, and consumption of endogenous antioxidants by these radicals may lead to a dramatic rise in intracellular ROS.

• Recent studies have provided evidence that indirect signaling pathways mediated by ROS can also cause cellular damage and death in cerebral ischemia and reperfusion..

Generation of oxygen radicals and clearance pathways (2)

• ROS are directly involved with cellular macromolecules such as lipids, proteins, and nucleic acids in oxidative damage in ischemic tissues, which leads to cell death.

• These constantly produced reactive oxygen species (ROS) are scavenged by superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase.

• SOD specifically processes superoxide anion (O2−) and produces H2O2, which

is then detoxified by catalase or GSHPx, and finally changed to water and superoxide. GSHPx is especially important for detoxifying H2O2 after cerebral isc

hemia and reperfusion.

• Hydroxyl radicals (−OH) may be generated from H2O2 through the Fenton reac

tion (H2O2 + Fe2+ → HO + Fe3+ + −OH).

• Other small molecular antioxidants, including glutathione (GSH), ascorbic acid, and α-tocopherol, are also involved in the detoxification of free radicals.

Superoxide dismutase (SOD)• SODs are specific antioxidant enzymes that detoxify O2

− and produce H2O2. dismutate O2

−, forming H2O2, which is scavenged by catalase or GSHPx at the expense of GSH

• SODs are major antioxidant enzymes based on cellular distribution and localization.

• Three SODs, copper/zinc SOD (SOD1), manganese SOD (SOD2), and extracellular SOD (ECSOD)– SOD1: a major cytosolic enzyme, constituted at approximately 0.1% of to

tal proteins in mammalian cells; extensively used in experimental studies; – SOD2 is a mitochondrial enzyme– ECSOD is an isoform that is localized in extracellular space, cerebrospina

l fluid, and cerebral vessels.

SOD in ischemic stroke

• SOD1: short half-life: 6 min in circulating blood ; cannot pass the blood-brain barrier or be taken up intracellularly, make it difficult to use for enzyme therapy in cerebral ischemia

• A modified enzyme with an increased half-life, polyethylene glycol-conjugated SOD1, has been successfully used to reduce infarct volume in rats that were subjected to focal cerebral ischemia. (He et al. Am J Physiol 265: H252–H256, 1993)

• Liposome-entrapped SOD1 has an increased half-life (up to 4.2 h), blood-brain barrier permeability and cellular uptake, and has been proven to be an effective treatment for reducing the severity of ischemic and traumatic brain injuries. (Imaizumi S et al. Stroke 21: 1312–1317, 1990)

Free radicals--Therapeutic approaches for human ischemia

• Diminishing the production of oxygen radicals

• Scavenging oxygen radicals

• Protecting the tissue from their effects.