Stroke prevention research. J. David Spence Stroke Prevention & Atherosclerosis Research Centre Robarts Research Institute London, Canada

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1 Stroke prevention research J. David Spence Stroke Prevention & Atherosclerosis Research Centre Robarts Research Institute London, Canada

2 Disclosures Grants for research from HSF, NIH, CIHR Grants for research from Pfizer, Merck, Pan American Labs Lecture fees from Pfizer, AstraZeneca, Merck, Novartis, Boehringer-Ingelheim Consulting fees from Novartis, Boehringer- Ingelheim Interest in

3 Medical research A career in medical research is non-linear Follow the questions where they lead Develop/adapt methods to do so Technological courage One answer leads to another question Persistence Patience! research is the ultimate in delayed gratification note the dates on the references

4 My research areas not discussed Pseudohypertension Effect of grapefruit on drug metabolism Vitamins to stroke by homocysteine Individualized therapy for hypertension Clinical pharmacology of drugs for stroke prevention Effects of therapy on 3D carotid plaque volume

5 4 key lectures The origin of a question Dr. Daria Haust atherosclerosis Dr. Margot Roach Flow disturbances Dr. C. Miller Fisher Strokes from high blood pressure due to small vessel disease, not atherosclerosis Dr. Fraser Mustard Atherosclerosis focal, where arteries bend and branch

6 My starting point Atherosclerosis occurs at branches and bends Related to flow disturbances Antihypertensive drugs might have different effects on flow disturbances, so Might have different effects on atherosclerosis First presented at Neurology Journal Club in Dr. Barnett s living room in ~ 1972

7 Effects of antihypertensive drugs on blood velocity Spence JD, Pesout AB, Melmon KL. Stroke 1977;8;

8 Effects of antihypertensive drugs on blood velocity Spence JD, Pesout AB, Melmon KL. Stroke 1977;8;

9 Effect of hydralazine vs. propranolol in hypertensive rabbits fed cholesterol Spence JD et al. Atherosclerosis 1984; 50:

10 Effect of hydralazine vs. propranolol in hypertensive rabbits fed cholesterol Spence JD et al. Atherosclerosis 1984; 50:

11 Assessing flow disturbances in human beings Spence JD Clin lnvestig Med 1989;12:82-89.

12 Wait a minute: We can see the artery wall!

13 We started with composite drawings of the plaques but one day in 1990 I asked Maria DiCicco RVT Maria, how do I know you re drawing the plaques the same way from one year to the next? Composite drawing of all plaques in extracranial carotids

14 Measurement of 2-D Plaque area* Well,..there is software in the machine I could measure the plaques if you want me to. What? Show me! * Invented in our lab in 1990 by Maria DiCicco, R.V.T.

15 We found an enormous dynamic range for total plaque area 79 yo woman 72 yo man Composite drawing of all plaques in extracranial carotids

16 Carotid Plaque Area as predictor of events 1,686 patients in our Atherosclerosis Prevention Clinic followed up to 5years During mean followup of years: 94 MI, 45 strokes, 44 deaths (27 vascular). Spence JD, Eliasziw M, DiCicco M et al. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:

17 Baseline Carotid plaque area as a predictor of events Stroke, MI, Death (after adjustment for risk factors*) *Age, sex, SBP, tchol, pack-yrs, thcy, diabetes, Rx lipids and BP Stroke 2002; 33:

18 Distribution of carotid plaque area by age groups and sex Spence JD. Nature Clinical Practice Neurology 2006;2:

19 Plaque progression despite therapy doubles the risk* Medical treatment was failing in half the cases, and they were at double the risk: we needed to do better! *Adjusted for Age, sex, SBP, tchol, pack-yrs, thcy, diabetes, Rx lipids and BP Stroke 2002; 33: JDS

20 Paradigm change: Treating arteries, not risk factors Instead of treating risk factors to target, since 2003 we treat patients more intensively if their plaque is progressing, regardless of their level of LDL or other risk factors i.e. since 2003 our target is now plaque regression

21 Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure

22 Benefit of carotid endarterectomy Symptomatic severe stenosis: 2-yr reduction of stroke death from 26% to 9% Asymptomatic: 5-yr risk reduction 10% to 5% NNT to prevent 1 stroke in 2 years 1 : NNT Symptomatic severe >70% age<75 6 Symptomatic severe >70% age>75 3 Symptomatic moderate 50-69% 15 Asymptomatic 67-83* Predicated on 3% surgical risk, and historical medical therapy 1.Barnett HJM. CMAJ 2004;171: 473-4

23 TCD microembolus detection 319 ACS patients between 2000 and % had microemboli 1-year Stroke Risk No Emboli Emboli 1% 15.6% 95% CI ( ) (4.1-79) p< Spence JD et al. Stroke 2005; 36:

24 Stroke risk over 2 years by baseline microembolic status Spence JD et al. Stroke 2005;36:

25 Biology of ulcers vs microemboli We obtained a grant from HSFO with Rob Hegele and Quim Madrenas to study inflammatory biomarkers and gene expression in carotid stenosis patients with ulcers, microemboli or neither. After 2 years we had only found 7 patients with microemboli; there should have been 20. Where had the microemboli gone? Hypothesis: Had our new paradigm caused microemboli to disappear because more intensive therapy stabilized plaque? We therefore studied prevalence of microemboli in ACS and rate of plaque progression in our clinic patients, before and after the paradigm change in 2002

26 Methods: 468 patients with ACS 199 before Jan 1, 2003, 269 since 2003 All had baseline microembolus detection by TCD All followed for at least one year Database closed July 1, ,328 patients followed in our prevention clinics plaque measurements in successive years Rate of plaque progression per year computed by year, from 1997 to 2007

27 Decline of microemboli with more intensive medical therapy < 5% of ACS patients can now benefit from carotid endarterectomy or stenting 11% 2.2% P<0.001 Spence JD et al. Arch Neurol. 2010;67:180-6

28 Annual rate of plaque progression in ACS patients before and since 2003 P< n= 346 Spence JD et al. Arch Neurol. 2010;67:180-6

29 Kaplan-Meier Survival free of stroke, death, MI logrank test p< logrank test p< Spence JD et al. Arch Neurol. 2010;67:180-6

30 Decline in events in ACS with more intensive medical therapy No emboli Microemboli p Before 2003 Since 2003 p* n=431 n=37 n=199 n=269 Stroke in year 1 1.4% 10.3% % 1% Stroke in year 2 1.8% 18.5% % 0% MI in year 1 2.2% 6.9% % 0.5% MI in year 2 1.4% 3.2% % 0.5% Death in year 1 2.8% 10.3% %% 2.4% Death in year 2 2.1% 3.7% % 0% CEA year 1 1.4% 12.9% % 1.9% CEA year 2 0.3% 3.7% % 0% Stroke, death or CEA 1 st 2 years Stroke, death, MI or CEA 1 st 2 years 6.5% 32.4% < % 4.5% < % 32.4% < % 5.2% < Spence JD et al. Arch Neurol. 2010;67:180-6

31 Carotid plaque measurement Summary Plaque measurement is useful for: Managing patients Stratifying risk Managing resources Encouraging patients to follow regimen Monitoring success of therapy Genetic research Quantitative traits for linkage studies Studying effects of new therapies Much smaller sample size x duration Proof of concept studies in human subjects Dose-finding studies

32 Ulceration as categorical variable Grade: 0 ulcers 1-2 ulcers 3-5 ulcers >5 ulcers

33 Ulceration vs microembol in ACS Madani A.Spence JD. Neurology 2011 Aug 23;77(8):

34 At least 90% of ACS patients should be treated only medically The treatment of choice for ACS should be intensive medical therapy Less than 5% of ACS patients can benefit from revascularization Only those with microemboli should be considered for endarterectomy or stenting

35 3D ultrasound measurement of carotid plaque volume and vessel wall volume Developed with Dr. Aaron Fenster and Dr. Grace Parraga at Robarts

36 First measurement of carotid plaque volume 1994

37 Rendered plaque volume

38 Disk segmentation method

39 Vessel Wall Volume Egger M, Spence JD, Fenster A, Parraga G. Validation of 3D Ultrasound Vessel Wall Volume: An Imaging Phenotype of Carotid Atherosclerosis. Ultrasound Med Biol Jun;33(6):

40 Progression of plaque volume predicts events Stroke 2013;44:

41 Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure

42 The Future Imaging vulnerable plaque Bogiatzi C, Cocker M, Beanlands R, Spence JD. Identifying high-risk asymptomatic carotid stenosis. Expert Opin Med Diagnostics 2012, Vol. 6, No. 2:

43 CAIN Project 2 Histological validation of preoperative imaging of vulnerable plaque in patients scheduled for carotid endarterectomy 3D US ulceration Plaque composition by MRI and 3D US 3D histology Ulcer 3D US plaque roughness Plaque inflammation by PET/CT

44 Dietary cholesterol is important High cholesterol (1021 mg/day), high saturated fat (P/S ratio 0.4) diet increased serum cholesterol (23%) by raising the cholesterol concentration in very low-density lipoproteins (59%), low-density lipoproteins (15%), and high-density lipoproteins (30%). 1 Variation in cholesterol rather than the proportions of saturated and polyunsaturated fat had the most influence on LDL-cholesterol levels. Among non-caucasians it was the only significant factor. 2 1.Tan MH, Dickinson MA, Albers JJ, Havel RJ, Cheung MC, Vigne JL. The effect of a high cholesterol and saturated fat diet on serum high-density lipoprotein-cholesterol, apoprotein A-I, and apoprotein E levels in normolipidemic humans. Am J Clin Nutr 1980 December;33(12): Fielding CJ, Havel RJ, Todd KM et al. Effects of dietary cholesterol and fat saturation on plasma lipoproteins in an ethnically diverse population of healthy young men. J Clin Invest 1995 February;95(2):611-8.

45 Propaganda is communication aimed at influencing the attitude of a community toward some cause or position. As opposed to impartially providing information, propaganda in its most basic sense, presents information primarily to influence an audience. Propaganda often presents facts selectively (thus lying by omission)...

46 Egg propaganda Egg marketers were charged by the FDA with false advertising 20 years ago, and convicted They lost their appeal They ve spent hundreds of $millions on propaganda since then

47 Egg propaganda Rests on A red herring Fasting cholesterol is what matters And a half-truth eggs can be part of a healthy diet for healthy people

48 Egg yolks in the Health Professionals Study 37, 851 men aged 40 to 75 years at study outset and 80, 082 women aged 34 to 59 years at study outset, free of cardiovascular disease, diabetes, hypercholesterolemia, or cancer. 866 CHD, 258 strokes in men in 8 yrs FU 939 CHD, 563 strokes in women /14 yrs No significant risk in healthy participants, but: In new onset diabetics, RR of 1egg/day risk vs. <1/week men, 2.02 [95%, ; P for trend =.04] women, 1.49 [ ; P for trend =.008]). Hu FB et al. JAMA. 1999;281:

49 Egg yolks and CHD risk Nationally representative sample of 9,734 adults aged 25 to 74 followed 20 years Adjustment for age, sex, race, serum cholesterol, BMI, diabetes mellitus, SBP, education and smoking No risk in healthy participants, but in diabetics: 6 eggs per week vs <1 - CHD RR 2.0 (95% CI ) Qureshi AN et al. Med Sci Monit. 2007;13(1):CR1-8

50 Egg yolks and CHD risk Greek diabetic cohort per 10 grams of egg per day (1/6 th of an egg) overall mortality HR 1.31 (95% CI 1.07 to 1.60) cardiovascular mortality HR 1.54 (95% CI, 1.20 to 1.97) A daily egg increased coronary risk 5-fold Trichopoulou A et al. J Intern Med 2006;259(6):

51 Egg yolks are not OK Recommended cholesterol intake for high-risk patients 1 : <200mg/day 1 large egg yolk contains ~237 mg of cholesterol Egg yolks only increase ordinary LDL by 10%, but increase LDL oxidation by 34-39% 2,3 Eggs increase risk of diabetes and events in metaanalysis 4 1. Catapano AL et al. Atherosclerosis 2011;217 Suppl 1:S Levy Y et al. Ann Nutr Metab 1996;40: Schwab US et al. Atherosclerosis 2000;149(1): Li Y, et al. Atherosclerosis (2):524-30

52 Fasting lipids: the carrot in the snowman Diet is about the postprandial state, not about fasting lipids Spence JD. Can J Cardiol 2003;19:890-2.

53 Dietary Toxins: Hardee s Monster Thickburger 2/3 pound beef 4 strips bacon 3 slices cheese Mayo DF 1420 Calories 107 g Fat 210 mg cholesterol

54 Egg yolks Egg whites good source of protein 1 large egg yolk contains ~237mg of cholesterol -More than the Hardee s Monster Thickburger - more than 4 days worth of meat for the Cretan Mediterranean diet, which is the more effective at reducing heart attacks and strokes. Stopping egg yolks after the heart attack would be like quitting smoking after the lung cancer is diagnosed

55 What about omega-3 eggs? They have omega-3 oils from feeding flax to chickens, but just about as much cholesterol Better you should eat the flax seed, and leave the chicken out of it!

56 Egg-yolk years as a risk factor Independent of Sex, smoking, blood pressure, BMI, diabetes and serum cholesterol Spence JD, Jenkins DJA, Davignon J. Atherosclerosis 2012; 224:

57 Effect of egg yolks independent of other risk factors Spence JD, Jenkins DJA, Davignon J. Atherosclerosis 2012; 224:

58 Effect of egg yolk and smoking additive Smoking and egg yolk consumption Little-smoking little-egg eaters (Pack-years <10, egg yolks quintiles 1 or 2) n=95 Little-smoking big egg eaters (Pack-years<10, egg yolks quintile 4 or 5) n=284 Smoking littleegg eaters (Pack-years >10, egg yolks quintile 1 or 2) n= 185 Smoking big egg-eaters (pack-yrs >10, egg yolks top quintile) n= 155 Plaque area (mm2) Increase in plaque area Comparator (mm 2 ) Ratio Comparator Spence JD, Jenkins DJA, Davignon J. Atherosclerosis 2013; 227:

59 Dietary recommendations for vascular patients NO egg yolks egg whites, Egg Creations Meat of any animal: 4 oz. every OTHER day High intake of olive oil, Canola oil Whole grains, vegetables, fruit, legumes Avoid deep fried foods, hydrogenated oils (trans fats) To accomplish this, patients need to think of their meatless day not as a punishment day, but as a gourmet cooking class day: Having fun learning how to make healthy eating tasty Spence JD. How to prevent your stroke. Vanderbilt University Press 2006

60 Where to next? Randomized trial of treating arteries vs. usual care Extremes of atherosclerosis and Genomics Intestinal microbiome

61 Atherosclerosis only half explained by traditional risk factors Spence JD. Nature Clin Pract Neurol 2006; 2:

62 Quantitative traits: - unexplained atherosclerosis - unexplained protection Reduces by ¾ the sample sizes needed for genomic studies A way of finding new therapeutic targets Lanktree MB et al. Circ Cardiovasc Genet 2010; 3: Spence JD. Atherosclerosis 2012;223:

63 Intestinal microbiome a biological and medical revolution 3 trillion bacteria in our intestines they convert nutrients to metabolites that get into our bloodstream and have profound metabolic effects on us Economist, August 18-24, 2012

64 Intestinal microbiome and diet L-carnitine from red meat and lecithin from egg yolks Converted by intestinal bacteria to trimethylamine; oxidized in the liver to TMAO Tang WHW et al. N Engl J Med 2013;368:

65 TMAO increases stroke/death/mi Tang WHW et al. N Engl J Med 2013;368:

66 Intestinal microbiome and atherosclerosis Recruit 500 patients at the extremes of atherosclerosis Obtain samples of blood, urine, stool, dietary info Extract and bank DNA for future genomic studies as funded Extract DNA from stool Analyze the profile of bacteria in patients with unexplained atherosclerosis vs. Protection from atherosclerosis Study their complete metabolic profile Find panels of good bacteria to repopulate the intestine of patients with bad bacteria that are causing excess atherosclerosis An entirely new way to prevent heart attacks and strokes!

67 It takes a team SPARC team to recruit patients and obtain samples London Regional Genomics Centre to extract and bank DNA Dr. Emma Allen-Vercoe at Guelph to extract and bank the DNA from stool Dr. Greg Gloor to analyze the intestinal populations using RNA methods Dr. Jonathan Swann at Reading University, UK metabolomics Dr. Gregor Reid make sense of the findings, design panels of therapeutic bacteria

68 Acknowledgements 3-D Ultrasound technology Genetics Drs. Aaron Fenster, Grace Parraga Dr. Rob Hegele Measurements Lab Manager 2-D : Maria DiCicco RVT Tisha Mabb 3-D: Craig Ainsworth, Funding Anthony Landry, Chris Blake, NINDS Micaela Egger, Christiane Mallet, Silvia Riccio HSF Ontario Bernard Chiu, Shayna McKay, Adam Krasinsky CHRI Ulcers Dr. Vadim Beletsky, Jeremy Mason Plaque composition Jeremy Mason, Dr. Joseph Awad TCD Study Dr. Arturo Tamayo MRI Dr. Claudio Munoz Dr. Brian Rutt Scanning PET/CT Maria DiCicco RVT Dr. Jean-Luc Urbain Janine Desroches RVT Dr. Ting Lee

69 Acknowledgements Maria DiCicco Aaron Fenster Grace Parraga R.V.T. Ph.D. Ph.D. Plaque area Plaque volume Vessel wall volume Plaque roughness, texture 3D U/S

70 Medical scientists are like astronomers but in thrall to the wonders of biology and medicine Advances in Genetics and Imaging are our Hubble Telescope It is the joy and the obligation of the physician to be a perpetual student. Sir William Osler Google: Orion photos: M4; Orion nebula

71 robarts.ca/sparc