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Recent Advances in Pathogenesis, Assessment, and Treatment of Atherosclerosis


Recent Advances in Pathogenesis, Assessment, and Treatment of Atherosclerosis

J David Spence. F1000Res.


In recent years, there have been a number of advances in the pathogenesis and treatment of atherosclerosis and in assessing prognosis in carotid atherosclerosis. Risk stratification to improve vascular prevention by identifying patients most likely to benefit from intensive therapy is much improved by measuring carotid plaque burden. In patients with asymptomatic carotid stenosis, a number of modalities can be used to identify the 10-15% who could benefit from endarterectomy or stenting. Transcranial Doppler embolus detection, echolucency and ulceration on 3D ultrasound, intraplaque hemorrhage on magnetic resonance imaging (MRI), and reduced cerebrovascular reserve are useful already; new approaches including plaque texture on ultrasound and imaging of plaque inflammation and early calcification on positron emission tomography/computed tomography (PET/CT) are in development. The discovery that the intestinal microbiome produces vasculotoxic metabolites from dietary constituents such as carnitine in meat (particularly red meat) and phosphatidylcholine from egg yolk and other sources has revolutionized nutritional aspects of vascular prevention. Because many of these vasculotoxic metabolites are removed by the kidney, it is particularly important in patients with renal failure to limit their intake of red meat and egg yolk. A new approach to lowering low-density lipoprotein (LDL) cholesterol by blocking the action of an enzyme that destroys LDL receptors promises to revolutionize vascular prevention once less costly treatments are developed, and a new approach to vascular prevention-"treating arteries instead of risk factors"-shows promise but requires randomized trials. These advances all promise to help in the quest to prevent strokes in high-risk patients.

Keywords: LDL; Transcranial Doppler embolus detection; atherosclerosis; carnitine; carotid plaque; cholesterol.

Conflict of interest statement

Competing interests: J. David Spence In the past 2 years has received lecture honoraria/consulting fees from Bayer and Bristol Myers Squibb and has performed contract research with Pfizer, Bayer, Bristol Myers Squibb, Acasti Pharma, POM Wonderful, CVRx, AGA Medical, and Gore. He is an officer and shareholder of Vascularis Inc., a company seeking to market software for vascular risk reclassification based on measurement of carotid plaque burden.

No competing interests were disclosed.


Figure 1.
Figure 1.. Pathways linking dietary phosphatidylcholine, intestinal microbiota, and incident adverse cardiovascular events.
Ingested phosphatidylcholine (lecithin), the major dietary source of total choline, is acted on by intestinal lipases to form a variety of metabolic products, including the choline-containing nutrients glycerophosphocholine, phosphocholine, and choline. Choline-containing nutrients that reach the cecum and large bowel may serve as fuel for intestinal microbiota (gut flora), producing trimethylamine (TMA). TMA is rapidly further oxidized to trimethylamine N-oxide (TMAO) by hepatic flavin-containing monooxygenases (FMOs). TMAO enhances the accumulation of cholesterol in macrophages, the accumulation of foam cells in artery walls, and atherosclerosis, all factors that are associated with an increased risk of heart attack, stroke, and death. Choline can also be oxidized to betaine in both the liver and the kidneys. Dietary betaine can serve as a substrate for bacteria to form TMA and presumably TMAO. Reproduced by permission of the Massachusetts Medical Society from: Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL: Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. N Engl J Med 2013, 368(17): 1575–1584.
Figure 2.
Figure 2.. Procedure for determining plaque volumes from 3D ultrasound images.
a) An approximate axis of the vessel is selected in a longitudinal view (colored line) and the internal elastic lamina and lumen boundary are outlined (yellow). b) Using the surfaces generated by the vessel contours and the 3D ultrasound image, the position of the bifurcation (BF; yellow arrow) is determined and marked. The axis of the vessel is selected based on the bifurcation point and marked along the branch as far as the plaque can be measured (colored line). This axis will be used as a reference for distance measurements. c) All plaques within the measurable distance are outlined, different colors being used for each separate plaque to aid in identification. d) Volumes are calculated for each plaque, and surfaces of the vessel wall and plaques are generated to better visualize the plaques in relation to the carotid arteries. Reproduced by permission of Wolters Kluwer from: Ainsworth CD, Blake CC, Tamayo A, Beletsky V, Fenster A, Spence JD: 3D ultrasound measurement of change in carotid plaque volume: a tool for rapid evaluation of new therapies. Stroke 2005, 36(9): 1904–1909.
Figure 3.
Figure 3.. Vessel wall volume.
Vessel wall volume segmentation. ( a) The transverse view of the common carotid artery shows the vessel boundary outlined in red and the lumen boundary outlined in yellow. ( b) The 3D ultrasound image volume is sliced longitudinally to reveal the vessel and lumen boundaries in the common, internal, and external carotid branches. The internal carotid artery vessel and lumen boundaries are shown in blue and pink, respectively. Reproduced by permission of Elsevier from: Egger M, Spence JD, Fenster A, Parraga G: Validation of 3d ultrasound vessel wall volume: an imaging phenotype of carotid atherosclerosis. Ultrasound Med Biol 2007, 33(6): 905–914.
Figure 4.
Figure 4.. Transcranial Doppler embolus detection.
Microembolus in a patient with asymptomatic carotid stenosis. The upper channel is an M-mode image of an embolus in the middle cerebral artery; the lower panel shows the high-intensity transit signal in the Doppler channel. Besides the visual appearance of the microembolus, a characteristic clicking sound is heard. Reproduced by permission of the Society for Vascular Ultrasound from: Spence JD. Transcranial Doppler: uses in stroke prevention. The Journal for Vascular Ultrasound 2015, 39(4): 183–187.
Figure 5.
Figure 5.. Carotid ulcer volume.
Measurement of ulcer volume and ulcer depth. Contours of ulcers were traced and depth of ulcers measured in cross-sectional views. Each slice had a thickness of 1 mm; ulcer volume was computed from the sum of the volumes of all slices in which ulceration was traced. Reproduced by permission of Wolters Kluwer from: Kuk M, Wannarong T, Beletsky V, Parraga G, Fenster A, Spence JD: Volume of carotid artery ulceration as a predictor of cardiovascular events. Stroke 2014, 45(5): 1437–1441.
Figure 6.
Figure 6.. Carotid plaque texture.
Texture for two plaques in the same vessel with a different appearance. In a total of 50 runs of sparse Cox regression (5× 10-fold cross-validation) on changes in texture, Laws edge-edge-ripple (EER) was selected in the model 49 times, and Laws spot-spot-ripple (SSR) 48 times. Reproduced by permission of Wolters Kluwer from: van Engelen A, Wannarong T, Parraga G, Niessen WJ, Fenster A, Spence JD, de Bruijne M: Three-dimensional carotid ultrasound plaque texture predicts vascular events. Stroke 2014, 45(9): 2695–2701.
Figure 7.
Figure 7.. Imaging of vulnerable plaque by positron emission tomography/computed tomography (PET/CT).
NaF PET/CT imaging of left and right internal carotid arteries of active calcification in a 72-year-old symptomatic patient evaluated at the University of Ottawa Heart Institute. Upper row: evidence of NaF uptake with small foci of calcification on CT in the left internal carotid symptomatic culprit vessel. There is a mismatch between the region of NaF uptake and calcification on CT. Lower row: evidence of calcium nodules with matched NaF uptake at the right internal carotid artery. Reproduced by permission of Springer from: Cocker MS, Mc Ardle AB, Spence JD, Lum C, Hammond RR, Ongaro DC, McDonald MA, Dekemp RA, Tardif JC, Beanlands RS: Imaging atherosclerosis with hybrid [18F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: what Leonardo da Vinci could not see. J Nucl Cardiol 2012, 19(6): 1211–1225.

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