cerebral blood flow; stroke

Cerebral Blood FlowAnd

Ischemic Brain Disease

BERNARDO L. CONDE, M.DBERNARDO L. CONDE, M.D..Professor of Neurology & Psychiatry Professor of Neurology & Psychiatry

Faculty of Medicine & SurgeryFaculty of Medicine & Surgery

University of Santo TomasUniversity of Santo Tomas

Normal MetabolismNormal Metabolism

All tissues require constant sources of All tissues require constant sources of oxygen and oxidizable substratesoxygen and oxidizable substrates

The brain requires –The brain requires – OxygenOxygen 3.5 ml/100 grams3.5 ml/100 grams GlucoseGlucose 5.5 mg/100 grams5.5 mg/100 grams Blood Flow Blood Flow 50 ml of blood/100 50 ml of blood/100

gramsgrams

The BRAIN extractsThe BRAIN extracts

10% (30 umol/100 gram per ml) of glucose 10% (30 umol/100 gram per ml) of glucose from the blood.from the blood.

50% (156 umol/100 gram per minute) of 50% (156 umol/100 gram per minute) of the oxygen delivered to the brain.the oxygen delivered to the brain.

Regulation of Cerebral Metabolic RateRegulation of Cerebral Metabolic Rate

Brain consumes about 1/5 of the total Brain consumes about 1/5 of the total body oxygen consumption.body oxygen consumption.

Continuous cerebral circulation is Continuous cerebral circulation is absolutely required to provide sufficient absolutely required to provide sufficient oxygen.oxygen.

1. Anaerobic Glycolysis

GlucosePyruvic acid

CO

Pyruvic acid Acetyl CoA

2. Krebs (citric acid) Cycle

3. Respiratory (electron-transport) chain

10 NADH → 10 NAD +

2 FADH3 → 2 FAD + H2O

Five Levels of Vaso-regulation of the Five Levels of Vaso-regulation of the Cerebro-Vascular SystemCerebro-Vascular System

AutoregulationAutoregulation Regulation by intrinsic neural pathwaysRegulation by intrinsic neural pathways Regulation by extrinsic neural pathwaysRegulation by extrinsic neural pathways Metabolic couplingMetabolic coupling Regulation by the endotheliumRegulation by the endothelium

Factors Increased CBF Decreased CBF

Extrinsic

Systemic blood pressure MAP <50 to 70 mmHg

Cardiovascular function Cardiac arrhythmias; orthostatic hypotension; loss of carotid sinus and aortic arch reflexes

Blood viscosity Anemia Polycythemia

Intrinsic

State of the cerebral vasculature

Arteriovenous malformation Atherosclerosis

Intracranial CSF pressure Increased intracranial pressure

Cerebral autoregulatory mechanism

Myogenic factors Decreased intraluminal pressure (vasodilation)

Increased intraluminal pressure (vasoconstriction)

Neurogenic factors Parasympathetic stimulation (vasodilation)

Sympathetic stimulation (vasoconstriction)

Biochemical-metabolic factors

Increased CO2 (vasodilation)Decreased O2 (vasodilation)Decreased pH (acidosis) (vasodilation)Lactic acidosis (vasodilation)

Decreased CO2 (vasoconstriction)Increased O2 (vasoconstriction)Increased pH (alkalosis) (vasoconstriction)Lactic acidosis (vasodilation)

Pathogenesis of the PLAQUEPathogenesis of the PLAQUE

““RESPONSE TO INJURY” Hypothesis:RESPONSE TO INJURY” Hypothesis: The plaque is initiated by endothelial damage, The plaque is initiated by endothelial damage,

and the development of the plaque is the and the development of the plaque is the result of proliferation of smooth muscle cells result of proliferation of smooth muscle cells in response to mitogenic agents, LDL, and in response to mitogenic agents, LDL, and platelet-derived growth factors.platelet-derived growth factors.

ENDOTHELIAL INJURYENDOTHELIAL INJURY

Includes actual desquamation of Includes actual desquamation of endothelial cells as well as functional endothelial cells as well as functional disturbances that result in alterations in disturbances that result in alterations in thrombo-resistance or inability of the thrombo-resistance or inability of the endothelium to act as effective barrier for endothelium to act as effective barrier for the transfer of macromolecules into the the transfer of macromolecules into the vessel wall.vessel wall.

Systemic Factors affecting the Systemic Factors affecting the CEREBRO-VASCULAR SYSTEMCEREBRO-VASCULAR SYSTEM

HypertensionHypertension Diabetes mellitusDiabetes mellitus HypercholesterolemiaHypercholesterolemia Cigarette smokingCigarette smoking Obesity Obesity

Probable Mechanism of Action of Probable Mechanism of Action of Risk Factors at the Cellular LevelRisk Factors at the Cellular Level

HYPERTENSIONHYPERTENSION Increased endothelial permeability to LDL due Increased endothelial permeability to LDL due

to:to: Increased artery tensionIncreased artery tension ““Trap door effect”of angiotensinTrap door effect”of angiotensin Platelet sticking (NE induced?) with release of Platelet sticking (NE induced?) with release of

vasoactive aminesvasoactive amines Especially bad when added to Especially bad when added to

hypercholesterolemiahypercholesterolemia

HYPERCHOLESTEROLEMIAHYPERCHOLESTEROLEMIA Increased level of circulating LDL damage Increased level of circulating LDL damage

endothelium and carry cholesterol into artery endothelium and carry cholesterol into artery wall;wall;

Lipid (cholesterol) is “trapped”, accumulates Lipid (cholesterol) is “trapped”, accumulates in smooth muscle cells or is bound to their in smooth muscle cells or is bound to their extracellular product;extracellular product;

Lead to cell proliferation and/or necrosis, Lead to cell proliferation and/or necrosis, increased collagen formation, etc.increased collagen formation, etc.


Cell Membrane CholesterolCell Membrane Cholesterol

Ischemic Stroke Risk Increases Ischemic Stroke Risk Increases With Serum CholesterolWith Serum Cholesterol

• Estimate adjusted for age, sex, race, hypertension, index year, time to cholesterol measurement, SBP and DBP, coronary heart disease, atrial fibrillation, diabetes, tobacco use, and use of statins

CI=confidence interval; SBP=systolic blood pressure; DBP=diastolic blood pressure.Adapted from Tirschwell DL et al. Neurology. 2004;63:1868-1875.

Total Ischemic Stroke (95% CI)

Total Cholesterol (mmol/L)

Total Cholesterol (mg/dL)

4 5 6 7 8

4

3

2

1

0.5

Od

ds

Rat

io (

95%

Cl)

Mea

n va

lue

of lo

wes

t qu

intil

e

150 175 200 225 250 275 300 325

(n=1242)

DIABETESDIABETES CHO induced hyperlipidemia (VLDL) along CHO induced hyperlipidemia (VLDL) along

with unknown factors stimulating arterial with unknown factors stimulating arterial media cell proliferation.media cell proliferation.


CIGARETTE SMOKINGCIGARETTE SMOKING Damage to cells of artery wall due to:Damage to cells of artery wall due to:

Circulating CO;Circulating CO; Platelet agglutination (NE induced?);Platelet agglutination (NE induced?); Lipid mobilization (NE induced?) leading to Lipid mobilization (NE induced?) leading to

hyperlipidemia and;hyperlipidemia and; Increased lipid in artery wallIncreased lipid in artery wall


OBESITYOBESITY Elevated blood lipids;Elevated blood lipids; Increased incidence of diabetes and Increased incidence of diabetes and

hypertension;hypertension; Poor cardiac reserve and increased work of Poor cardiac reserve and increased work of

the heart.the heart.


Local Factors affecting the Local Factors affecting the CEREBRO-VASCULAR SYSTEMCEREBRO-VASCULAR SYSTEM

Geometry of the vesselGeometry of the vessel Shear stress of flowing bloodShear stress of flowing blood

Hypertension Hypertension 6.01 ( 4.48 – 8.05)6.01 ( 4.48 – 8.05) Diabetes Diabetes 1.60 (1.10 – 2.32)1.60 (1.10 – 2.32) Atrial Fibrillation Atrial Fibrillation 1.91 ( 0.51 – 7.19)1.91 ( 0.51 – 7.19) MI MI 4.67 (1.18 - 18.52)4.67 (1.18 - 18.52) RHD RHD 3.69 (1.05 -12.99 ) 3.69 (1.05 -12.99 ) Smoking Smoking 1.36 (1.00 - 1.86) 1.36 (1.00 - 1.86) Habitual Snoring Habitual Snoring 3.37 (2.49 - 4.58)3.37 (2.49 - 4.58) StressStress 1.69 (1.25 – 2.29)1.69 (1.25 – 2.29) Freq.Alcohol Intake Freq.Alcohol Intake 1.75 (1.14 –2.70)1.75 (1.14 –2.70)

RIFASAF

Local Risk Factors for Stroke Among Filipinos

A. Roxas for PNA-DOH Risk factors for stroke among Filipinos (RIFASAF). Phil J Neur 2002; 6:1-7.

RISK FACTORS FOR RISK FACTORS FOR ATHEROTHROMBOSISATHEROTHROMBOSIS

Atherothrombotic ManifestationsAtherothrombotic Manifestations

(MI, Ischemic STROKE, Vascular Death)(MI, Ischemic STROKE, Vascular Death)

ATHEROSCLEROSATHEROSCLEROSISIS

Hypercoagulable statesHomocysteinemiaDiabetes

Obesity

Genetics

HyperlipidemiaHypertensionInfection ?

Age

Gender

Lifestyle (smoking, diet, lack of exercise)

Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis

No symptomsNo symptoms SymptomsSymptoms

Time (y)Time (y)

SymptomsSymptoms

Lesion initiationLesion initiation

Ischemic HeartIschemic HeartDiseaseDisease

CerebrovascularCerebrovascularDiseaseDisease

PeripheralPeripheralVascularVascularDiseaseDisease

Atherogenesis & Atherothrombosis: Atherogenesis & Atherothrombosis: A Progressive ProcessA Progressive Process

CLINICALLY CLINICALLY SILENTSILENTCLINICALLY CLINICALLY SILENTSILENT

ANGINA, TIA, ANGINA, TIA, CLAUDICATIONS, CLAUDICATIONS,

PADPAD

ANGINA, TIA, ANGINA, TIA, CLAUDICATIONS, CLAUDICATIONS,

PADPAD

MYOCARDIAL MYOCARDIAL INFARCTIONINFARCTIONMYOCARDIAL MYOCARDIAL INFARCTIONINFARCTION

ISCHEMIC STROKEISCHEMIC STROKEISCHEMIC STROKEISCHEMIC STROKE

CRITICAL LEG CRITICAL LEG ISCHEMIAISCHEMIA

CRITICAL LEG CRITICAL LEG ISCHEMIAISCHEMIA

CARDIOVASCULAR CARDIOVASCULAR DEATHDEATH

CARDIOVASCULAR CARDIOVASCULAR DEATHDEATH

INCREASING AGEINCREASING AGEINCREASING AGEINCREASING AGE

Atheromas are not filled merely with lipids, but Atheromas are not filled merely with lipids, but also contain cells whose functions critically also contain cells whose functions critically influence atherogenesis:influence atherogenesis:

Intrinsic Vascular Wall Cells:

Endothelium

Smooth Muscle Cells

Inflammatory Cells:

Macrophages

T Lymphocytes

Mast Cells

Cell Types in the Human AtheromaCell Types in the Human Atheroma

Monocyte/Monocyte/MacrophageMacrophage

T-lymphocytesT-lymphocytesTunicaMedia

Intima

Smooth musclecells

EndotheliumEndothelium

Leukocyte–EndothelialLeukocyte–Endothelial Adhesion MoleculesAdhesion Molecules

MonoMonoTT

BBPMNPMN

Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis

AttachmentAttachment

PenetrationPenetration



Activation

Molecular Mediators of Molecular Mediators of AtherogenesisAtherogenesis

M-CSFMCP-1

VCAM-1


Division

Anatomy of the AtheroscleroticAnatomy of the Atherosclerotic PlaquePlaque

LumenLipidCore

Fibrous cap

Shoulder

Intima

MediaElasticlaminæ

Internal

External

Platelet AdhesionPlatelet Adhesion

When blood vessels are injured, their When blood vessels are injured, their endothelial lining is disrupted exposing the endothelial lining is disrupted exposing the subendothelial matrix to the blood. subendothelial matrix to the blood. Platelets make contact with and spread Platelets make contact with and spread upon this matrix in a process known as upon this matrix in a process known as adhesion.adhesion.

Thrombotic Reactions to Thrombotic Reactions to Vascular InjuryVascular Injury

Endothelial disruption rapidly leads to Endothelial disruption rapidly leads to platelet adhesion, degranulation and platelet adhesion, degranulation and recruitment to form an enlarging recruitment to form an enlarging thrombotic mass.thrombotic mass.

Recruitment of platelets into forming Recruitment of platelets into forming thrombus requires that GPIIb/GPIIIa thrombus requires that GPIIb/GPIIIa complex undergoes conformational complex undergoes conformational change to become expressed as change to become expressed as fibrinogen receptor.fibrinogen receptor.

ADP: A Key Mediator of ADP: A Key Mediator of Platelet ActivationPlatelet Activation

FIBRINOGEN BINDING FIBRINOGEN BINDING SITESITE


FIBRINOGENFIBRINOGEN

PLATELET PLATELET RECRUITMENTRECRUITMENT

PLATELET PLATELET RECRUITMENTRECRUITMENT



PLATELET AGGREGATIONPLATELET AGGREGATIONPLATELET AGGREGATIONPLATELET AGGREGATION

FIBRINOGENFIBRINOGEN

PLATELET PLATELET ADHESIONADHESIONPLATELET PLATELET ADHESIONADHESION

INTERNAINTERNAL ADPL ADP

INTERNAINTERNAL ADPL ADP

EXTERNAEXTERNAL ADPL ADP

EXTERNAEXTERNAL ADPL ADP

ADP

ADP

ADP

OTHER OTHER AGONISTAGONIST

SS

OTHER OTHER AGONISTAGONIST

SS

PLATELET PLATELET AGGREGATIONAGGREGATION

PLATELET PLATELET AGGREGATIONAGGREGATION

Signal Response Coupling in Signal Response Coupling in PlateletsPlatelets

TXATXA22

ARACHIDONIARACHIDONIC ACIDC ACID

PHOSPHOLIPASE PHOSPHOLIPASE A2A2

PHOSPHOLIPASE PHOSPHOLIPASE CC

DIACYLGLYCEROLDIACYLGLYCEROL

C-C-KINASEKINASEGRANUGRANU

LELE

SECRETIONSECRETIONSECRETIONSECRETION

ACTIVATIONACTIVATIONACTIVATIONACTIVATION

AGGREGATIONAGGREGATIONAGGREGATIONAGGREGATION

DENSEDENSE

TUBULETUBULE

RR RR

AAAAIIbIIb IIIaIIIa

IPIP33 PIPPIP22

Ca Ca 2+2+

FIBFIB

GG

Ca Ca 2+2+

Physiologic Antithrombotic Physiologic Antithrombotic MechanismsMechanisms

Endothelial cells productsEndothelial cells products Heparan sulfateHeparan sulfate

Stimulates activity of antithrombin IIIStimulates activity of antithrombin III AT III inhibits coagulation factors II; IX; X; XI; XIIAT III inhibits coagulation factors II; IX; X; XI; XII

Physiologic Antithrombotic Physiologic Antithrombotic MechanismsMechanisms

Thrombomodulin bind thrombinThrombomodulin bind thrombin Tm+Th+factor V stimulates activation of Tm+Th+factor V stimulates activation of

protein Cprotein C Protein C inactivates factor V; VII; and Protein C inactivates factor V; VII; and

neutralizes the inhibitor of tPAneutralizes the inhibitor of tPA

Thrombin InactivationThrombin Inactivation

Vasodilatation-Thrombin increases Vasodilatation-Thrombin increases production of nitric oxide (endothelial production of nitric oxide (endothelial derived relaxing factor which induces derived relaxing factor which induces vasodilatation locally and inhibits platelet vasodilatation locally and inhibits platelet function directly and synergistically with function directly and synergistically with prostacyclin)prostacyclin)

Thrombin InactivationThrombin Inactivation

Anti-thrombin III inhibits thrombin and Anti-thrombin III inhibits thrombin and coagulation factors IXa; VIIa; and Xacoagulation factors IXa; VIIa; and Xa

Normal Control of THROMBOSIS Normal Control of THROMBOSIS

THROMBINTHROMBINTHROMBINTHROMBIN

FIBRIN FIBRIN CLOTCLOT

FIBRIN FIBRIN CLOTCLOT

PLATELETSPLATELETSPLATELETSPLATELETS

HEPARINHEPARINHEPARINHEPARINTHROMB0-THROMB0-MODULINMODULIN

THROMB0-THROMB0-MODULINMODULIN

PLASMINOGEPLASMINOGENN

PLASMINOGEPLASMINOGENN

PLASMINPLASMINPLASMINPLASMIN

LYSISLYSISLYSISLYSIS

tPAtPAtPAtPA

ACTIVATED ACTIVATED TXA2/NOTXA2/NO

ACTIVATED ACTIVATED TXA2/NOTXA2/NO

PROTEIN CPROTEIN CPROTEIN CPROTEIN C

PROTEIN CaPROTEIN CaPROTEIN CaPROTEIN Ca

TFPITFPITFPITFPI

VIIa-IXaVIIa-IXaVIIa-IXaVIIa-IXa

XaXa

VV

SSATIIIATIIIATIIIATIII

THANK YOU VERY MUCH

Thrombosis of a Disrupted Atheroma, the Cause Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results of Most Acute Coronary Syndromes, Results from:from:

Weakening of the fibrous cap

Thrombogenicity Thrombogenicity of the lipid coreof the lipid core

Illustration courtesy of Michael J. Davies, MD

Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis

Thrombus Fibrous cap

1 mmLipid core

Illustration courtesy of Frederick J. Schoen, MD, PhD

Matrix Metabolism and Integrity of the Matrix Metabolism and Integrity of the Plaque’s Fibrous CapPlaque’s Fibrous Cap

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

+ + + +

++

–

Synthesis Breakdown

Lipid core

IL-1TNF-MCP-1M-CSF

FibrouscapIFN-IFN-

CD-40L

Collagen-degradingCollagen-degradingProteinasesProteinases

Tissue Tissue FactorFactorProcoagulantProcoagulant

CD40 ligand on activated platelets CD40 ligand on activated platelets

triggers an inflammatory reaction of triggers an inflammatory reaction of

endothelial cellsendothelial cells

Henn V, et al. Nature. 1998;391:591-594.

Inflammation Can Promote ThrombosisInflammation Can Promote Thrombosis

PlateletPlatelet

TissueTissueFactorFactor

FibrinogenFibrinogenvia gp via gp llb/lllallb/llla

FibrinFibrinCD40LCD40LPlatelet-Platelet-

FibrinFibrinThrombusThrombus

FibrinopeptidesFibrinopeptides

PlateletPlatelet

Treatment of Mixed HyperlipidemiaTreatment of Mixed Hyperlipidemia

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

High LDL-C and TGsHigh LDL-C and TGsHigh LDL-C and TGsHigh LDL-C and TGs

Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Drug TherapyDrug TherapyDrug TherapyDrug Therapy

Achieve the LDL-C goalAchieve the LDL-C goal11STEPSTEP

Achieve the non-HDL-C goalAchieve the non-HDL-C goalIncrease LDL-C lowering orIncrease LDL-C lowering orAdd a fibrate, niacin or fish oilsAdd a fibrate, niacin or fish oils

22STEPSTEP

Progression of Drug Therapy for Progression of Drug Therapy for

LDL-C LoweringLDL-C Lowering

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Visit 1Visit 1 Visit 2Visit 2 Visit 3Visit 3 F/U VisitsF/U Visits

Start Start statin or statin or bile acid bile acid resin or resin or nicotinic nicotinic

acidacid

Consider higher Consider higher dose of the dose of the

statin or add a statin or add a bile acid resin bile acid resin

or nicotinic acidor nicotinic acid

66wkswksInitiate Initiate

LDL-LDL-lowering lowering drug drug therapytherapy

66wkswks

qq4–64–6momo

If LDL goal If LDL goal not achieved, not achieved, intensify LDL-intensify LDL-lowering lowering therapytherapy

If LDL goal not If LDL goal not achieved, achieved, drug therapy drug therapy or refer to a or refer to a lipid specialistlipid specialist

Monitor Monitor response response and and adherence adherence to therapyto therapy

If LDL goal If LDL goal has been has been achieved, achieved, treat other treat other lipid risk lipid risk factorsfactors

cerebral blood flow; stroke

Documents

oxygen glucose blood

cerebral blood flow

brain extracts

sufficient oxygen

constant sources of

mg100 grams

ml100 grams

blood100 grams