Post on 13-Nov-2014
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.
Probable Mechanism of Action of Probable Mechanism of Action of Risk Factors at the Cellular LevelRisk Factors at the Cellular Level
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.
Probable Mechanism of Action of Probable Mechanism of Action of Risk Factors at the Cellular LevelRisk Factors at the Cellular Level
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
Probable Mechanism of Action of Probable Mechanism of Action of Risk Factors at the Cellular LevelRisk Factors at the Cellular Level
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.
Probable Mechanism of Action of Probable Mechanism of Action of Risk Factors at the Cellular LevelRisk Factors at the Cellular Level
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
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
Activation
Molecular Mediators of Molecular Mediators of AtherogenesisAtherogenesis
M-CSFMCP-1
VCAM-1
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
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
FIBRINOGEN BINDING FIBRINOGEN BINDING SITESITE
FIBRINOGENFIBRINOGEN
PLATELET PLATELET RECRUITMENTRECRUITMENT
PLATELET PLATELET RECRUITMENTRECRUITMENT
FIBRINOGEN BINDING FIBRINOGEN BINDING SITESITE
FIBRINOGEN BINDING FIBRINOGEN BINDING SITESITE
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