J. David Spence MD, FRCPC, FAHA

 Spence is Professor of Neurology and Clinical Pharmacology and Director of the Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute at Western University in London, Canada.

Although we have seen significant decline in mortality due to ischemic stroke, atherosclerosis remains a significant problem in the US. In fact, despite research and medical advances, some patients appear to be non-responders, leaving a significant number of patients at heightened risk for negative outcomes. The notion of “resistant atherosclerosis,” points to possible breakthroughs in research and treatment.


People whose arteries keep getting worse despite achieving consensus targets for low-density lipoprotein (LDL)-C (eg, below 1.8 mmol/L; 70 mg/dL) have resistant atherosclerosis.1 In other words, there are other factors besides LDL-C causing the disease. This is evidenced by measuring carotid plaque burden annually to assess response to therapy.
My colleagues and I developed the measurement of carotid total plaque area (TPA) in 1990 for risk classification, genetic research, and management of patients.

 We measure TPA routinely in our prevention clinics since 1995, but 3-dimensional measurement of carotid plaque volume and vessel wall volume are now becoming possible. Resistant atherosclerosis is important because patients with a high plaque burden are at high risk. Those with a TPA higher than 119 mm2 (the top quartile of TPA) have a 20% 5-year risk of stroke/death/myocarcial infarction, after adjusting for coronary risk factors.

 Those with plaque progression despite treatment have twice the risk of those with stable plaque or regression.


Neither achieved LDL-C nor change in LDL-C was strongly correlated with plaque progression or regression.

 Nearly half the patients (47.5%) in our study had plaque progression despite achieving target LDL-C, and the distribution of LDL-C levels did not differ among patients with progression, regression, or stable plaque. Both age and increased serum creatinine significantly increased resistance to treatment; ie, patients in the top quartile of age or serum creatinine were more likely to have plaque progression despite achieving LDL-C < 1.8 mmol/L.

Renal impairment might aggravate atherosclerosis because of several factors, including elevated levels of total homocysteine (tHcy, a clotting factor that increases the risk of stroke, particuarly in atrial fibrillation), asymmetric dimethylarginine (ADMA, a nitric oxide antagonist), and thiocyanate (a powerful oxidant). Levels of the toxic products of the intestinal microbiome may also play a role; these include trimethylamine n-oxide (TMAO, produced by the intestinal bacteria from carnitine in red meat, and phosphatidylcholine in egg yolk), and toxic products of amino acid metabolism including p-cresyl sulfate, indoxyl sulfate, and indole acetic acid.

The effect of age is partly due to renal impairment (the average eGFR [estimated glomerular filtration rate] is less than 60 by age 80), but it may also be due to factors such as mitochondrial aging (with impaired ability to deal with oxidative stress), and telomere shortening.


Another way that aging may contribute to resistant atherosclerosis is unrecognized metabolic B12 deficiency, which increases the levels of tHcy [total homocysteine]. Among patients who attend our stroke prevention clinic, metabolic B12 deficiency is present in 10% of patients younger than age 50, and 30% of patients older than age 70. By age 80, 40% of patients have a tHcy level higher than 14 µmol/L.

B vitamins clearly prevent stroke, and it is crucial to monitor at risk patients for B12 defiency. Metabolic B12 deficiency needs to be detected and treated, however, rather than using cyanocobalamin we need to use methylcobalamin. In early trials, harm from cyanocobalamin among patients with renal failure obscured the benefit among those with good renal function.

For an in-depth discussion of resistant artherosclerosis see Yang and colleagues

 and my article on risk factor control in stroke prevention.

 However, since we don’t know how to treat most of the unknown factors, we need to intensify the treatments that are available (


In 2003 we implemented the “treating arteries instead of treating risk factors” approach. The target of therapy is not just to achieve a normal blood pressure and an LDL-C below target; it is to stop progression of plaque or achieve regression. In 2010 we reported that among high-risk patients with asymptomatic carotid stenosis, this approach reduced the 2-year risk of stroke or myocardial infarction by more than 80%. In other words, it removed much of the residual risk that is seen with usual therapy.

The implementation of this approach made it apparent that some patients have resistant atherosclerosis.
Some patients require really low levels of LDL-C to stop progression of plaque. I have more than 100 patients with LDL-C below 0.5 mmol/L (19 mg/dL) and a few with LDL-C below 0.3 mmol/L (12 mmol/L), because that’s what it took to stop the progression of artherosclerosis.


In order to know whether lipid-lowering therapy is successful, it is not enough to measure the achieved LDL-C. To know what is happening to the arteries it is necessary to measure plaque burden. Showing patients pictures of their plaque getting worse markedly improves their adherence to diet, smoking cessation, and medication; a key component of “treating arteries.”

1. Spence JD, Solo K. Resistant atherosclerosis: the need for monitoring of plaque burden. 

2. Spence JD. Technology insight: ultrasound measurement of carotid plaque--patient management, genetic research, and therapy evaluation. 

3. Spence JD. Measurement of carotid Plaque burden. 

4. Spence JD, Eliasziw M, DiCicco M, et al. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. 

5. Yang C, Bogiatzi C, Spence JD. Risk of stroke at the time of carotid occlusion. 

6. Spence JD. Intensive risk factor control in stroke prevention. 

7. Korcarz CE, DeCara JM, Hirsch AT, et al. Ultrasound detection of increased carotid intima-media thickness and carotid plaque in an office practice setting: does it affect physician behavior or patient motivation? 

8. Spence JD. Statins do not cause intracerebral hemorrhage. Neurology. 2012;79(11):1076-7.

9. Spence JD. Recent advances in preventing stroke recurrence. 

10. Spence JD. Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke. 

11. Spence JD. Homocysteine lowering for stroke prevention: unravelling the complexity of the evidence. 

12. Spence JD, Yi Q, Hankey G. B Vitamins in stroke prevention: time to reconsider. 

13. Akintunde A, Nondi J, Gogo K, et al. Physiological phenotyping for personalized therapy of uncontrolled hypertension in Africa. 

14. Rayner BL, Spence JD. Hypertension in blacks: insights from Africa. 

15. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. 

Articles

The notion of “resistant atherosclerosis,” points to possible breakthroughs in research and treatment.

J. David Spence MD, FRCPC, FAHA

Articles

Taking a New Look at Resistant Atherosclerosis