Spedali Civili di Brescia University of Brescia Italy

Spedali Civili di Brescia – University of Brescia, Italy Valutazione del rischio cerebrovascolare nell’iperteso Prof Enrico Agabiti Rosei Clinica Medica – University of Brescia, Italy

Stroke Mortality vs Usual BP by Age at risk: Systolic Blood Pressure Stroke Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 Diastolic Blood Pressure 80 -89 ys 256 80 -89 ys 70 -79 ys 128 70 -79 ys 60 -69 ys 64 60 -69 ys 32 50 -59 ys 16 16 8 8 4 4 2 2 1 1 0 0 120 140 160 180 Usual Systolic BP (mm Hg) 70 80 90 100 110 Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet. 2002; 360: 1903 -1913

Redon et al, Eur Heart Journal 2011

Risk Factors for Stroke ü Office BP üCentral BP ü 24 hour BP ü BP variability (day/night, day/day, 24 hours variability, BP morning rise)

2013; 346: f 2573 Conclusion QStroke provides a valid measure of absolute stroke risk in the general population of patients free of stroke or transient ischaemic attack as shown by its performance in a separate validation cohort. QStroke also shows some improvement on current risk scoring methods, CHADS 2 and CHA 2 DS 2 VASc, for the subset of patients with atrial fibrillation for whom anticoagulation may be required. Further research is needed to evaluate the cost effectiveness of using these algorithms in primary care.

Fattori di rischio per ictus ischemico - Non modificabili: • Eta • Fattori genetici • Fattori etnici - Modificabili: ben documentati • ipertensione arteriosa; • alcune cardiopatie (in particolare, fibrillazione atriale); • diabete mellito; • iperomocisteinemia; • ipertrofia ventricolare sinistra; • stenosi carotidea; • fumo di sigaretta; • eccessivo consumo di alcool; • ridotta attivita fisica; • dieta; • ipercolesterolemia; • obesita; SPREAD 2012

Sono stati descritti altri fattori che probabilmente aumentano il rischio di ictus • sindrome metabolica; • alcune cardiopatie (forame ovale pervio, aneurisma settale); • placche dell’arco aortico; • uso di contraccettivi orali; • terapia ormonale sostitutiva; • emicrania; • anticorpi antifosfolipidi; • fattori dell’emostasi; • infezioni; • uso di droghe; • inquinamento atmosferico • sindrome delle apnee ostruttive da sonno SPREAD 2012

CRP and RR of stroke Ridker 1997 PHS Ridker 2000 WHS Gussekloo 2000 CRP in top quartile Leiden Ford 2000 NHANES Rost 2001 Framingham men women 0. 0 0. 5 1. 0 2. 0 3. 0 4. 0 Relative risk of stroke Ridker, Circulation 2002 5. 0

Atherosclerosis 2014

The study evaluated the associations between hourly changes in air pollution and the risks of several types of cardiovascular disease. Results—Suspended particulate matter exposure 0 to <6 hours before the case events was associated with risks of onset of cardiovascular and cerebrovascular disease Odds ratios after 1 interquartile range increase in suspended particulate matter exposure were - 1. 04 (95% confidence interval, 1. 01– 1. 06) for cardiovascular disease - 1. 04 (95% confidence interval, 1. 00– 1. 08) for cerebrovascular disease. - We observed an elevated risk of hemorrhagic as well as ischemic stroke, but the risk was slightly higher for hemorrhagic stroke, and this elevation was persistent. - Women tended to have higher effect estimates “Conclusions—This study provides further evidence that particulate matter exposure increases the risks of onset of cardiovascular and cerebrovascular disease (including hemorrhagic stroke) shortly after exposure. ” Yorifuji et al, Stroke 2014

Journal of Hypertension 2011 Multicenter, cross-sectional, survey included 2973 patients with a known diagnosis of hypertension or migraine in a general practitioner setting in Italy Results - 517 patients (17%) suffered from hypertension–migraine comorbidity - 1271 (43%) suffered from hypertension only - 1185 (40%) from migraine only “…Conclusion This cross-sectional study indicates that the prevalence of comorbidity hypertension-migraine is substantial and that patients with comorbidity have a higher probability of history of cerebrovascular events, compared to hypertensive patients…”

Spector et al, Am J Med. 2010 - The pooled adjusted odds ratio of ischemic stroke comparing migraineurs to non-migraineurs using a random effects model was 2. 30 (95% CI, 1. 91 -2. 76). Stroke. 2013 - Overall pooled adjusted effect estimate of hemorrhagic stroke in subjects with any migraine versus control subjects was 1. 48 (95% CI, 1. 16– 1. 88; P=0. 002)

Predictors of stroke ü ü ü Left ventricular hypertrophy Carotid intima media thickness Aortic pulse wave velocity Small resistance arteries Microalbuminuria

LV mass and risk of stroke in the Framingham Heart Study Bikkina et al, JAMA 1994

431 patients with first ischemic stroke and 434 stroke-free control subjects underwent 2 -dimensional transthoracic echocardiography - concentric hypertrophy carried the greatest stroke risk (adjusted OR, 3. 5; 95% CI, 2. 0 to 6. 2) - followed by eccentric hypertrophy (adjusted OR, 2. 4; 95% CI, 2. 0 to 4. 3). - concentric remodeling carried slightly increased stroke risk (adjusted OR, 1. 7; 95% CI, 1. 0 to 2. 9). - increased LV relative wall thickness was independently associated with stroke after adjustment for LV mass (OR, 1. 6; 95% CI, 1. 1 to 2. 3). Di Tullio et al, Stroke. 2003

Increased LV mass and subsequent new-onset AF STRONG HEART STUDY New onset AF 76/3182 subjects over 8 yrs OR 3. 1 (95% CI 2. 1 -4. 6), p = 0. 001 AF % BRESCIA COHORT New onset AF 22/436 HT patients over 10 yrs; OR 2. 4 (95% CI 0. 94 -6. 3), p = 0. 06

Pulse pressure and left atrial size Age-adjusted prevalence of left atrial enlargement according to 8 -year average pulse pressure in men and women. Vaziri S et al. Hypertension 1995; 25: 1155 -1160

CHS Association Between LA Size and Incidence of AF LA Dimension Relative Risk (95% CI) £ 3. 00 cm 1—Reference 3. 01– 4. 00 cm 1. 54 (0. 80 – 2. 96) 2. 58 (1. 35 – 4. 94) 4. 01– 5. 00 cm 4. 05 (1. 96 – 8. 35) >5. 00 cm 0 1 2 Psaty et al. Circulation 1997; 96: 2455 -2461. 3 4 5 6 7 8 9

Hazard ratio (HR) for Myocardial infarction or Stroke per 0. 1 mm difference in common carotid IMT Event Hazard Ratio (CI 95%) N of pts AMI 1. 1* 1. 08 -1. 13 30162 Stroke 1. 13* 1. 10 -1. 16 34335 * Adjusted for age, sex and other risk factors Lorenz M et al, Circulation 2007; 115: 459 -467

Two-year risk of ischemic stroke in the territory of the symptomatic carotid artery according to degree of carotid stenosis and angiographic appearance of the plaque surface in patients randomized to medical treatment only Irregular stenosis Smooth stenosis Rothwell, Stroke 2000

Aortic stiffness is a predictor of fatal strokes 1715 hypertensives ; mean follow-up : 7. 9 yrs Laurent S et al. Stroke 2003 Proportion of patients surviving 1. 00 0. 95 Kaplan-Meyer P<0. 01 0. 90 PWV < 11. 4 m/s PWV > 11. 4 m/s 0. 00 0 10 Time(Year) 20

Ben Schlomo et al, J Am Coll Cardiol 2014; 63: 636– 46

SUBJECTS Subjects 245 subjects from a general population in a small town in Northern Italy ümean age at baseline: 56± 4 years (range 43 -57 years) ü 42% males and 58% female ühypertension in 46% (20% treated) - CF PWV (Complior) - Local carotid PWV (Artlab system) Clinica Medica, University of Brescia

Framingham risk score Aortic PWV (m/s) Carotid PWV (m/s) r p 10 -year risk of CHD event 0. 28 <0. 001 0. 08 ns 10 -year risk of MI event 10 -year risk of STROKE event 0. 26 <0. 001 0. 04 ns 0. 36 <0. 001 0. 26 <0. 001 10 -year risk of CVD event 0. 32 <0. 001 0. 13 ns 10 -year risk of CHD death 0. 24 <0. 01 0. 05 ns 10 -year risk of CVD death 0. 28 <0. 001 0. 11 ns Clinica Medica, University of Brescia

Methods—Carotid arterial strain and compliance, distensibility and stiffness indices, pressure–strain, and Young elastic moduli were measured in 10407 individuals using ultrasound - Over a mean follow-up of 13. 8 years, 1267 incident CHD and 383 ischemic stroke events occurred. - After full adjustment for risk factors and carotid intima-media thickness, all arterial stiffness parameters (carotid arterial strain; arterial distensibility; stiffness indices; pressure–strain; Young elastic moduli, except arterial compliance): - were significantly associated with incident stroke but not with CHD - Conclusions—After adjusting for cardiovascular RF, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events despite that the 2 outcomes sharing similar risk factors. Stroke. 2012

Aortic Stiffness and Cerebral Small-Vessel Disease Henskens et al Hypertension. 2008; 52: 1 -2

Aortic Stiffness and Cerebral Small-Vessel Disease N= 23 never treated hypertensive patients 16 M, 7 F, age range 37 -72 years Internal Medicine , University of Brescia

LARGE ARTERY STIFFENING AS A LINK BETWEEN CEREBRAL LACUNAR INFARCTION AND RENAL ALBUMINURIA Hashimoto J, Aikawa T, Imai Y. Am J Hyertens 2008, 21: 1304 -309 351 general adults aged > or =50 years Microvascular damage in the brain (lacunar infarction) and kidney (albuminuria) can be interrelated with each other, probably due to stiffening of large arteries

12 studies, with a total of 48 596 participants and 1263 stroke events Stroke 2010

Consequences of Vascular remodeling in Hypertension Small size arteries M L M Increase in BP Structural changes M/L Media/Lumen Vasodilatory Capacity M L M Sierra, Coca et al. Cardiol Clin Pract 2012; 4: 1 -12, modified Blood Flow to Target Organs Stroke Cognitive disturbance

STRUCTURAL ALTERATIONS OF CEREBRAL SMALL ARTERIES IN PATIENTS WITH ESSENTIAL HYPERTENSION Media to lumen ratio of cerebral small resistance arteries M * Cerebral artery of a hypertensive patient (Z. L. 62 years) Wire micromyograph M/L=0. 098 internal diameter 310 μm Pressure micromyograph M/L=0. 083 internal diameter 296 μm N=8 *=p<0. 05 vs. normal controls

Hypertension 2013; 61: 130 -136

Large/small artery cross talk in hypertension Target organ damage Small artery remodeling wall/lumen ratio and rarefaction CV events Target organ damage central PP mean BP arterial stiffness Large artery remodeling

- Fattori di rischio per stroke tradizionali e nuovi oltre l’ipertensione arteriosa - Danno d’organo cardiaco preclinico e stroke - Danno d’organo vascolare preclinico e stroke