1. RISK FACTORS & PATHOPHYSIOLOGY OF STROKE Christos Savopoulos Assistant Professor of Internal Medicine 1st Propedeutic Medical Department Aristotle University of Thessaloniki Department of Hypertension & Vascular Diseases AHEPA Hospital

2. Stroke accounts for 10% of all-cause mortality Cancer12% Stroke10% Accidents Respiratory infections 7% Respiratory infections 7% HIV/AIDS 5% Chronic obstructive pulmonary disease 5% Perinatal causes Diarrhoea Tuberculosis 3% 3% 4% 2% Malaria Coronary heart disease 13% American Stroke Association. Heart Disease and Stroke Statistics 2004 9% 27% Other causes Since 80s, a significant increase (> 2-fold ) has been noticed in incidence of stoke : 1–2 /1.000 people in USA, 2–2.5/1.000 in Western και 3–3.5/1.000 in Eastern Europe

4. Stroke is strongly correlated with age and CVRF existence 10% of strokes are fatal ~55% patients will experience a new & often more severe stroke or die within the next 5 years ~30% of survivors becomes disabled and/or develops vascular dementia «cross» cardiovascular risk! After a stroke: x2 - 3 risk for myocardial infarction In ~10% of patients with myocardial infarction, stroke will occur within the next 5 years Stroke is strongly correlated with age and CVRF existence 10% of strokes are fatal ~55% patients will experience a new & often more severe stroke or die within the next 5 years ~30% of survivors becomes disabled and/or develops vascular dementia «cross» cardiovascular risk! After a stroke: x2 - 3 risk for myocardial infarction In ~10% of patients with myocardial infarction, stroke will occur within the next 5 years Epidemiological data with clinical significance Framingham Heart Study; American Heart Association, Heart and Stroke Facts statistical update, Lees KR, et al. BMJ 2000;320:991–994; Hankey GJ, Warlow CP. Lancet 1999;354:1457–1463

5. Frequency of Stroke related to age & gender NHANES: 1999-2002 CDC/NCHS and NHLBI  Men  Women Non- modifiable Non- modifiable Risk Factors  Race: (e.g Afro-Americans increased risk)  Family history of stroke (inheritance ?)  History of stroke or myocardial infarction (Early recurrence is observed after embolic stroke: cardioembolism & stroke from extracranial atherosclerosis)

6. Modifiable Modifiable risk factors Hypertension Diabetes Dyslipidaemia Smoking Risk for embolic events in heart or carotid disease Hypertension Diabetes Dyslipidaemia Smoking Risk for embolic events in heart or carotid disease Obesity Insulin resistance Decreased physical activity Increased alcohol consumption Heart disease (CHD, CHF) Vasculitis (infectious or collagen diseases) Migraine Hypothyroidism Sleep apnoea syndrome Hematological disorders (Hypercoagulation or emboli) Predisposition for thrombotic events (Hyperhomocysteinemia, female hormones) Other Major

7. Major risk factors for cerebral and myocardial events Risk factors are the same in all atherothrombotic events such as Coronary disease, stroke and peripheral vascular disease, but with different importance in each condition, according to the specific role, biological features and mechanical stress of the respective vascular areas. Hypertension is more important in cerebrovascular disease compared to coronary heart disease, whereas the opposite concerns dyslipidemia. Risk factors are the same in all atherothrombotic events such as Coronary disease, stroke and peripheral vascular disease, but with different importance in each condition, according to the specific role, biological features and mechanical stress of the respective vascular areas. Hypertension is more important in cerebrovascular disease compared to coronary heart disease, whereas the opposite concerns dyslipidemia. Coronary Cerebral BP Cholesterol HDL smoking obesity Heart rate Other factors (viral, infectious SBP,DBP

8. 10yr risk for Stroke in Adults 55 yrs old according to basic Risk Factors (Framingham Heart Study) A B C D E F A B C D E F Systolic BP 95-105130-148130-148130-148130-148130-148 mmHg Diabetes no no yes yes yes yes Smoking no no yes yes yes yes Previous AF no no no no yes yes Previous CVD no no no no no yes Stroke 1991;22:312-318

9. Atherosclerosis From risk factors to endothelial injury & CVD Risk factors Oxidative stress Endothelial dysfunction NO Local mediatorsTissue ACE-Ang II PAI-1VCAM,ICAM, cytokines EndotheliumCollagen growth factors Proteinolysis LDL-CBP Cardiac failureSmokingDiabetes Vasocontraction Vascular injury & remodeling Plaque ruptureInflammationThrombosis CV Clinical events Gibbons GH. N Engl J Med 1994 Adhesion molecules VCAM: vascular cell adhesion molecule, ICAM: intercellular adhesion molecule PAI-1: plasminogen activator inhibitor 1

10. Lumen Media: Smooth muscle cell Collagen proteins Internal elastic laminae Endothelium Intima: External elastic laminae Normal Arterial Wall (intima, Media, Adventitia)

11. up-regulation of endothelial adhesion molecules greater permeability of the endothelium Leucocyte migration into the arterial wall Leucocyte adhesion Penetration of lipoproteins Endothelial dysfunction in atherosclerosis (Early changes)

12. Foam cells formation Adhesion and penetration of leucocytes T cells activation Migration of smooth muscle cells Platelets’ adhesion and coagulation Lipid core formation (fatty streak) in atherosclerosis

13. Formation of fibrous cap Accumulation of macrophages Formation of necrotic core Formation of atherosclerotic plaque (death & rupture of foam cells in fatty streak)

14. Rupture of plaque and thrombus formation (supsequent luminal occlusion)

15. Progression of atherosclerosis Healthy SubclinicalSymptomatic Threshold DecadesYears-Months Months-Days Plaque Intima Media Lumen Threshold Intima Media Plaque Thrombus Lumen HEALTH POLICY Diet and lifestyle changes HEALTH POLICY Diet and lifestyle changes PRIMARY PREVENTION Drug treatment PRIMARY PREVENTION Drug treatment SECONDARY PREVENTION Aggressive drug therapy SECONDARY PREVENTION Aggressive drug therapy

16. Pathophysiology of Stroke Brain injury Due to: Vascular occlusion or hemodynamic disturbances from intracranial or extracranial vascular injury (stenosis, splitting, vasculitis) Interruption of cerebral blood flow Neuronic death (infarct) when self regulation of blood flow and collateral circulation are insufficient Results to: Functional body disorders which are controlled by the damaged part of the brain Brain injury Due to: Vascular occlusion or hemodynamic disturbances from intracranial or extracranial vascular injury (stenosis, splitting, vasculitis) Interruption of cerebral blood flow Neuronic death (infarct) when self regulation of blood flow and collateral circulation are insufficient Results to: Functional body disorders which are controlled by the damaged part of the brain

17. Thromboembolic Brain infarct Brain vessel thrombosis Emboli from extracranial thrombosis TIA Intracerebral hemorrhage Willis cycle Arterio-venous Dysplasia HEMORRHAGIC ISCHEMIC

18. Incidence – Mortality of ischemic & hemorrhagic Stroke The majority of strokes are ischemic Incidence – Mortality of ischemic & hemorrhagic Stroke The majority of strokes are ischemic Ischemic strokes Hemorrhagic strokes Intracranial Subarachnoidal Hemorrhagic strokes Intracranial Subarachnoidal Mortality 1 st month % Thrombotic TIA Subcortical- lacunar Cardio or arterio-arterial embolic Thrombotic TIA Subcortical- lacunar Cardio or arterio-arterial embolic

19. Types-Pathogenesis of Stroke Thrombotic : occlusion or stenosis of the vessel with hemodynamic effects (> 70%) due to growth or rupture of atherosclerotic plaque & consequent thrombosis Embolic : emboli originate from heart, aortic arch & major cervical vessels : due to Small subcortical or lacunar infarcts : due to lipohyalinosis of small brain vessels (< 15mm diameter) in thalamus, pons, basal gaglia, in elderly patients with hypertension or diabetes Transient Ischemic Attacks (ΤΙΑ): «small» strokes due to temporarily reduced blood supply, secondary to small platelet emboli, which rapidly dissociate. Symptoms disappear within a few minutes to 24h. Appearance and incidence of TIA is a significant predictive factor for the vascular system’s state and the occurrence of a permanent stroke PRIND (PRolonged Ischemic Neurological Deficiency): is characterized by restoration of clinical symptoms within the first 3 weeks Thrombotic : occlusion or stenosis of the vessel with hemodynamic effects (> 70%) due to growth or rupture of atherosclerotic plaque & consequent thrombosis Embolic : emboli originate from heart, aortic arch & major cervical vessels : due to Small subcortical or lacunar infarcts : due to lipohyalinosis of small brain vessels (< 15mm diameter) in thalamus, pons, basal gaglia, in elderly patients with hypertension or diabetes Transient Ischemic Attacks (ΤΙΑ): «small» strokes due to temporarily reduced blood supply, secondary to small platelet emboli, which rapidly dissociate. Symptoms disappear within a few minutes to 24h. Appearance and incidence of TIA is a significant predictive factor for the vascular system’s state and the occurrence of a permanent stroke PRIND (PRolonged Ischemic Neurological Deficiency): is characterized by restoration of clinical symptoms within the first 3 weeks

20. Hemorrhagic Stroke: caused by thinning, aneurysmatic dilatation of vascular wall, rupture of small vessels, microaneurysms or arteriovenous dysplasia. It is often accompanied by rapid deterioration, increased endocranial pressure, mass effect, hydrocephalus. However, in those who manage to survive, less severe disability compared to ischemic strokes of equivalent extent occurs. Pervasive - global cerebral ischemia: represents cardiovascular dysfunction like cardiac arrest or severe hypotension and pervasive vascular lesions like chronic cerebral microangiopathy. It is usually due to hypertension and if it lasts only few minutes, the result is transient global amnesia. In case of longer duration, coma, vegetative state without voluntary mobility due to cortical injury or brain death with isoelectric line in the EEG but preservation of cardiac function, ensues. Hemorrhagic Stroke: caused by thinning, aneurysmatic dilatation of vascular wall, rupture of small vessels, microaneurysms or arteriovenous dysplasia. It is often accompanied by rapid deterioration, increased endocranial pressure, mass effect, hydrocephalus. However, in those who manage to survive, less severe disability compared to ischemic strokes of equivalent extent occurs. Pervasive - global cerebral ischemia: represents cardiovascular dysfunction like cardiac arrest or severe hypotension and pervasive vascular lesions like chronic cerebral microangiopathy. It is usually due to hypertension and if it lasts only few minutes, the result is transient global amnesia. In case of longer duration, coma, vegetative state without voluntary mobility due to cortical injury or brain death with isoelectric line in the EEG but preservation of cardiac function, ensues. Types-Pathogenesis of Stroke

21. The occlusion of a cerebral vessel is followed by formation of a central irreversible tissue necrotic lesion, where the brain blood flow is reduced < 15% (<20 ml/100gr/min), with a peripheral zone, the Penumbra (20 - 30 ml/100gr/min), where tissue is viable and functional disturbance is reversible due to partial preservation of blood supply via emissary vessels, if ischemia reverses on time Depending on the grade of blood flow reduction and its duration, after an ischemic interval, Penumbra becomes necrotic Experimental studies report that the infarct ιs formed 3-12 h after initiation of ischemia and continues to develop even after 24h, although in a much slower rate (24-72h <30% increase) The occlusion of a cerebral vessel is followed by formation of a central irreversible tissue necrotic lesion, where the brain blood flow is reduced < 15% (<20 ml/100gr/min), with a peripheral zone, the Penumbra (20 - 30 ml/100gr/min), where tissue is viable and functional disturbance is reversible due to partial preservation of blood supply via emissary vessels, if ischemia reverses on time Depending on the grade of blood flow reduction and its duration, after an ischemic interval, Penumbra becomes necrotic Experimental studies report that the infarct ιs formed 3-12 h after initiation of ischemia and continues to develop even after 24h, although in a much slower rate (24-72h <30% increase) Pathophysiology of ischemic infarct - Penumbra Penumbra Infarct

22. Decreased energy supply to the cerebral parenchyma with simultaneous decrease in Ο 2, Glucose and ATP production (25% of normal levels in the central area, 50- 70% in Penumbra) Anaerobic glycolysis and metabolic acidosis Release of excitative aminoacids (glutamino-acid) and inflammatory mediators in extracellular space, decreased energy production, ions and water intracellular entrance, increase of catabolic enzymes and free radicals, neuron cells oedema, cellular membrane injury and cytolysis Disturbance of regional blood flow autoregulation (regional vasodilation) and as a consequence it’s absolute dependency from systemic BP (thus when BP reduces, ischemia worsens) Angiogenic oedema around the ischemic area because of blood-brain barrier destruction (endothelial cell connections, 1-4 days after ischemia), may cause compressive effect and necrotic area expansion Decreased energy supply to the cerebral parenchyma with simultaneous decrease in Ο 2, Glucose and ATP production (25% of normal levels in the central area, 50- 70% in Penumbra) Anaerobic glycolysis and metabolic acidosis Release of excitative aminoacids (glutamino-acid) and inflammatory mediators in extracellular space, decreased energy production, ions and water intracellular entrance, increase of catabolic enzymes and free radicals, neuron cells oedema, cellular membrane injury and cytolysis Disturbance of regional blood flow autoregulation (regional vasodilation) and as a consequence it’s absolute dependency from systemic BP (thus when BP reduces, ischemia worsens) Angiogenic oedema around the ischemic area because of blood-brain barrier destruction (endothelial cell connections, 1-4 days after ischemia), may cause compressive effect and necrotic area expansion Pathophysiology of ischemic stroke Neuronal disturbances

23. Large hemispheric strokes (10-20% in the total of ischemic strokes) are due to middle cerebral artery occlusion Several mechanisms contribute to ischemic stroke evolution, the main being the clot expansion Other possible mechanisms during the first 48-72 h after ischemic stroke initiation are: - cerebral oedema development and space occupational action, - metabolic disturbances like hyperglycemia, hyponatremia, - hemorrhagic transformation, - fever (infection) aggravating ischemic neuron metabolism Large hemispheric strokes (10-20% in the total of ischemic strokes) are due to middle cerebral artery occlusion Several mechanisms contribute to ischemic stroke evolution, the main being the clot expansion Other possible mechanisms during the first 48-72 h after ischemic stroke initiation are: - cerebral oedema development and space occupational action, - metabolic disturbances like hyperglycemia, hyponatremia, - hemorrhagic transformation, - fever (infection) aggravating ischemic neuron metabolism Pathophysiology of ischemic stroke

24. Ischemic infarct: Frequently, up to 50%, there is delay in CT imaging within 48 h “Normal CT” at admission of an ischemic stroke with left hemiparesis| Large infarct in the area of middle brain artery causing compressive effect, 48h after admission

25. Hemorrhagic Stroke Admission CT of hemorrhagic stroke with left hemiparesis and persistent headacne Subdense appearance and severe compressive effect of extented oedema around hematoma, 48h after admission

26. Thank you for your attention!