Roadmap Consensus on Carotid Artery Plaque Imaging and Impact on Therapy Strategies and Guidelines: An International, Multispecialty, Expert Review and Position Statement.

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis.

Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.

High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension.

OBJECTIVES: Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important. METHODS: Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype). RESULTS: There were 14 nonsynonymous variants (NSVs) of CYP11B2: 3 previously described and associated with alterations in aldosterone synthase production (R87G, V386A, and G435S). Out of 14, 9 variants were found in all 9 patients sequenced. There were 4 NSV of GRK4 (R65L, A116T, A142V, V486A): at least one was found in all 9 patients; 3 were previously described and associated with hypertension. There were 3 NSV of SCNN1B (R206Q, G442V, and R563Q); 2 previously described and 1 associated with hypertension. NPPA was found to have 1 NSV (V32M), not previously described and NEDD4L did not have any variants. UMOD had 3 NSV: D25G, L180V, and T585I. CONCLUSIONS: A phenotypic approach to investigating the genetic architecture of RHT uncovered a surprisingly high yield of variants in candidate genes. These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke.

Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies.

As the incidence of metabolic syndrome increases, there is also a growing interest in finding safe and inexpensive treatments to help lower associated risk factors. L-carntine, a natural dietary supplement with the potential to ameliorate atherosclerosis, has been the subject of recent investigation and controversy. A majority of studies have shown benefit of L-C supplementation in the metabolic syndrome or cardiovascular risk factors. However, recent work has suggested that dietary L-C may accelerate atherosclerosis via gut microbiota metabolites, complicating the role of L-C supplementation in health.

High-risk asymptomatic carotid stenosis: ulceration on 3D ultrasound vs TCD microemboli.

OBJECTIVE: We compared microemboli on transcranial Doppler (TCD) with carotid ulcerations on 3D ultrasound (US) as an additional method for identifying the small proportion of patients with asymptomatic carotid stenosis (ACS) who can benefit from revascularization such as endarterectomy or stenting. METHODS: Patients with ACS (n = 253) with carotid stenosis >60% by Doppler ultrasound were studied prospectively with TCD embolus detection and 3D US to detect ulcers (the total number of ulcers in both internal carotids) and followed for 3 years. RESULTS: Mean age was 69.66 (SD 8.51) years; 11 (4%) had ≥3 ulcers (Ulcer 3), 11 (6%) had microemboli, and 25 (10%) had microemboli or ≥3 ulcers. Ulcer 3 patients were more likely to have a stroke or death in 3 years (18% vs 2%; p = 0.03), regardless of the side on which the ulcers were found. The 3-year risk of stroke or death was 20% with microemboli vs 2% without (p = 0.003). The annual rate of ipsilateral stroke was 0.8%. CONCLUSION: Adding 3D US detection of ulcers doubles (to 10%) the proportion of patients with ACS who may benefit from endarterectomy or stenting. However, until 3-year event rates of stroke or death with endarterectomy or stenting reach <2%, 90% of patients with ACS would be better treated medically until they develop symptoms, ulcers, or emboli.

Carotid atherosclerosis and a reduced likelihood for lowered cognitive performance in a Canadian First Nations population.

BACKGROUND: We investigated the associations among cardiovascular risk factors, carotid atherosclerosis and cognitive function in a Canadian First Nations population. METHODS: Individuals aged > or = 18 years, without stroke, nonpregnant and with First Nations status were assessed by the Trail Making Test Parts A and B. Results were combined into a Trail Making Test executive function score (TMT-exec). Doppler ultrasonography assessed carotid stenosis and plaque volume. Anthropometric, vascular and metabolic risk factors were assessed by interview, clinical examinations and blood tests. RESULTS: For 190 individuals with TMT-exec scores, the median age of the population was 39 years. Compared to the reference group, individuals with elevated levels of left carotid stenosis (LCS) and total carotid stenosis (TCS) were less likely to demonstrate lowered cognitive performance [LCS, odds ratio (OR): 0.47, 95% confidence interval (CI): 0.24-0.96; TCS, OR: 0.40, 95% CI: 0.20-0.80]. No effect was shown for plaque volume. In structural equation modeling, we found that for every 1-unit change in the anthropometric factor in kg/m(2), there was a 0.86-fold decrease in the percent of TCS (p < 0.05). CONCLUSIONS: Individuals with elevated levels of LCS and TCS were less likely to demonstrate lowered performance. There was some suggestion that TCS mediates the effect of anthropometric risk factors on cognitive function.

Intra-arterial thrombolysis of occluded middle cerebral artery by use of collateral pathways in patients with tandem cervical carotid artery/middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Cervical internal carotid artery (ICA) occlusion with middle cerebral artery (MCA) embolic occlusion is associated with a low rate of recanalization and poor outcome after intravenous thrombolysis. Prompt revascularization is required to prevent disabling stroke. We report our experience on acute ischemic stroke patients with tandem ICA or MCA occlusions treated with microcathether navigation and intra-arterial thrombolysis by use of collateral pathways including the posterior or anterior communicating arteries, or both pathways. MATERIALS AND METHODS: We retrospectively identified 8 patients with proximal ICA occlusion associated with MCA embolic occlusions treated with intra-arterial thrombolysis (IA rtPA). Access to the occluded MCA was obtained via catheter navigation through intact collateral pathways, including posterior communicating (PcomA) or anterior communicating (AcomA) arteries, without passing a microcathether through the acutely occluded ICA. We assessed clinical outcomes using modified Rankin scale (mRS) and National Institutes of Health Stroke Scale (NIHSS). RESULTS: Eight patients with a mean age of 57 +/- 4 years and median NIHSS of 14 were identified. Mean time from stroke onset to intra-arterial thrombolysis was 292 +/- 44 minutes. The MCA was revascularized completely in 5 of the 8 patients via collateral intra-arterial rtPA administration. All of the patients had a favorable outcome defined as a mRS of < or =2 or more at 1 and 3 months' follow-up after thrombolytic therapy. One patient had an asymptomatic petechial hemorrhage. CONCLUSION: In this small number of patients with tandem occlusions of the ICA and MCA, intra-arterial thrombolysis and recanalization of the MCA by use of collateral pathways to bypass the occluded ICA is a safe and efficacious therapeutic option.

3D ultrasound analysis of carotid plaque volume and surface morphology.

Morphological characterization of carotid plaques has been used for risk stratification and evaluation of response to therapy, evaluation of new risk factors, genetic research, and for quantifying effects of new anti-atherosclerotic therapies. We developed a 3D US system that allows detailed studies of carotid plaques in 3D. Our software includes 3D reconstruction, viewing, manual and semi-automated segmentation of carotid plaques, and surface morphology analysis to be used for quantitative tracking of plaque changes. We evaluated our plaque quantification software by examining plaque volume measurement accuracy, variability, and plaque surface morphology. We used vascular test phantoms to study segmentation accuracy, and used 48 3D US carotid plaques of patients ranging in size from 13.2 mm(3) to 544.0 mm(3) to study plaque volume measurement variability. We compared results from the semi-automated plaque measurements to the results obtained from manual measurements, which were used as the "gold" standard. We developed a surface plaque morphology quantification technique based on the segmented plaque surface curvature and used it to analyze plaques. Accuracy of plaque volume measurements for the simulated plaques ranged from 4.2% to 1.5% for volumes ranging from 68.5 mm(3) to 286 mm(3). The variability study showed that coefficients of variation in the measurement of plaque volume decreased with increasing plaque size for both inter- (90.8-3.9%) and intra-observer (70.2-3.1%) measurements over the plaque sizes measured. Surface morphology analysis showed that 1 mm ulceration could be quantified and monitored for changes over time. The automated plaque quantification approach showed a little higher intra-observer variability than the manual technique, and its performance was better for segmenting the wall than the lumen. Our results indicate that our approach is sensitive tool and can be used in studies of plaque progression and regression as it relates to atherosclerosis treatment effects and can be used effectively in longitudinal studies for direct measurement carotid plaque volume.

A non-rigid image registration technique for 3D ultrasound carotid images using a "twisting and bending" model.

Atherosclerosis at the carotid bifurcation resulting in cerebral emboli is a major cause of ischemic stroke. Most strokes associated with carotid atherosclerosis can be prevented by lifestyle/dietary changes and pharmacological treatments if identified early by monitoring carotid plaque changes. Sensitive monitoring of plaque changes in volume and morphology requires that 3D ultrasound (US) images of carotid plaque obtained at different time points be registered and evaluated for change. This registration technique should be non-rigid, since different head positions in image acquisitions cause relative bending and torsion in the neck, producing non-linear deformations between the images. We modeled the movement of the neck using a "twisting and bending model" with only six parameters for non-rigid registration. We used a Mutual Information (MI) based image similarity measure with the Powell optimization method as they have been used effectively in US image registration applications. For evaluation of our algorithm, we acquired 3D US carotid images from three subjects at two different head positions to simulate images acquired at different times. Then, we registered each image set using our "twisting bending model" based non-rigid registration algorithm. We calculated the Mean Registration Error (MRE) between the segmented vessel surfaces in the target image and the registered image using a distance-based error metric. We repeated the experiment with only rigid registration to compare the capabilities of the proposed algorithm in improving registration of 3D carotid US images. The average registration error was 1.03+/-0.23 mm using our non-rigid registration technique, while it was 1.50+/-0.50 mm when we applied the rigid registration alone.

Carotid endarterectomy--an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy combined with cardiac surgery, are also reviewed. METHODS: The authors selected nine important clinical questions. A systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from 2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from 2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. RESULTS: For several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at 5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5 years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing endarterectomy. CONCLUSIONS: Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis (Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not indicated for symptomatic patients with <50% stenosis (Level A). For asymptomatic patients with 60 to 99% stenosis, the benefit/risk ratio is smaller compared to symptomatic patients and individual decisions must be made. Endarterectomy can reduce the future stroke rate if the perioperative stroke/death rate is kept low (<3%) (Level A). Low dose aspirin (81 to 325 mg) is preferred for patients before and after carotid endarterectomy to reduce the rate of stroke, myocardial infarction, and death (Level A).

Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration.

Plasma total homocysteine (tHcy) concentration, an independent risk factor of atherosclerosis, has numerous genetic and environmental determinants. While the thermolabile polymorphism in MTHFR encoding methylenetetrahydrofolate reductase is the best-studied genetic factor associated with variation in plasma tHCy, other candidate genes are being evaluated. Recently, we discovered that cystathioninuria was caused by mutations in the CTH gene encoding cystathionine gamma-lyase, an enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway. We also identified a common single nucleotide polymorphism (SNP), namely c.1364G>T (S403I) in exon 12 of CTH. In the current analysis, we studied the association of genotypes of this SNP with plasma tHcy concentrations in 496 Caucasian subjects. CTH 1364T/T homozygotes had significantly higher mean plasma tHcy concentration than subjects with other genotypes, and the effect sizes of CTH and MTHFR genotypes were similar. The findings suggest that common variation in CTH may be a determinant of plasma tHcy concentrations.

Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease.

BACKGROUND AND PURPOSE: Blood pressure lowering in patients with a previous transient ischemic attack (TIA) or stroke reduces the risk of recurrent stroke and coronary vascular events. However, there is uncertainty about the risks and benefits in patients with severe carotid occlusive disease, particularly those with a carotid occlusion or bilateral > or =70% carotid stenosis in whom cerebral perfusion is often impaired and may depend directly on systemic blood pressure. Therefore, we studied the effect of carotid artery disease on the relationship between blood pressure and stroke risk in patients with recent TIA or stroke. METHODS: We compared the relationship between blood pressure (systolic and diastolic blood pressures, pulse pressure) and stroke risk in TIA and stroke patients with documented stenosis of at least 1 carotid artery [European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET)] with that in TIA and stroke patients with a low prevalence of carotid disease [United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial]. In ECST and NASCET, we also determined the relationship between blood pressure and stroke risk in patients with unilateral carotid occlusion and patients with bilateral > or =70% carotid stenosis. RESULTS: Stroke risk on medical treatment increased with blood pressure in ECST and NASCET, but the relationships were less steep than in the UK-TIA trial. The relationship between blood pressure and stroke risk was not affected by the presence of a unilateral carotid occlusion but was significantly affected by the presence of bilateral carotid stenosis > or =70% (interaction: systolic blood pressure, P=0.002; diastolic blood pressure, P=0.03; pulse pressure, P=0.003). In this group, the relationship was inverted because of the high stroke risks at lower blood pressures. This interaction was not present after carotid endarterectomy and was not present for the risk of myocardial infarction. CONCLUSIONS: The risk of stroke increases with blood pressure in the great majority of patients with symptomatic carotid artery disease, but the relationship is less steep than in other patients with TIA or stroke. The relationship is unaffected by unilateral carotid occlusion alone but is inverted in patients with bilateral > or =70% carotid stenosis, suggesting that aggressive blood pressure lowering may not be advisable in this group. These patients represent only a few percent of all patients with TIA or stroke but have a high risk of recurrent stroke.