Carotid Stenosis and Stroke: Historical Perspectives Leading to Current Challenges.

The carotid artery is unique; it is the only vessel to bifurcate into a bulb larger than itself. The history of its anatomic description, understanding of its pathophysiology and evolution of its imaging are relevant to current controversies regarding measurement of stenosis, surgical/endovascular therapies and medical management of carotid stenosis in stroke prevention. Treatment decisions on millions of symptomatic and asymptomatic patients are routinely based on information from clinical trials from over 30 years ago. This article briefly summarizes the highlights of past research in key areas and discuss how they led to current challenges of diagnosis and treatment.

Assessment of atherosclerosis: should coronary calcium score and intima-media thickness be replaced by ultrasound measurement of carotid plaque burden and vessel wall volume?

PURPOSE OF REVIEW: To describe the uses of vessel wall volume (VWV) and measurement of carotid plaque burden, as total plaque area (TPA) and total plaque volume (TPV), and to contrast them with measurement of carotid intima-media thickness (IMT) and coronary calcium (CAC). RECENT FINDINGS: Measurement of carotid plaque burden (CPB) is useful for risk stratification, research into the genetics and biology of atherosclerosis, for measuring effects of new therapies for atherosclerosis, and for treatment of high-risk patients with severe atherosclerosis. It is as predictive of risk as CAC, with important advantages. IMT is only a weak predictor of risk and changes so little over time that it is not useful for assessing effects of therapy. SUMMARY: Measurement of CPB and VWV are far superior to measurement of carotid IMT in many ways, and should replace it. Vessel wall volume can be measured in persons with no plaque as an alternative to IMT. There are important advantages of CPB over coronary calcium; CPB should be more widely used in vascular prevention.

Problem in the Recent American Heart Association Guideline on Secondary Stroke Prevention: B Vitamins to Lower Homocysteine Do Prevent Stroke.

In this article, we discuss a problem in the most recent American Heart Association guideline on secondary stroke prevention that apparently arose from the rules of evidence imposed on the guideline panel. We are told by the cochair of the panel that American Heart Association rules about guidelines for secondary prevention prohibited consideration of primary prevention studies and secondary analyses of secondary prevention studies. However, evidence-based medicine should consider all the best external evidence available and also clinical judgement. The most important problem in the guideline was the recommendation that B vitamins to lower homocysteine do not prevent recurrent stroke. When considering all the best external evidence, it is clear that B vitamins do prevent stroke, but in the early secondary stroke prevention studies, the benefit of B vitamins in participants with good renal function was apparently offset by harm from cyanocobalamin among participants with renal failure (level B-R evidence). We review the evidence that B vitamins should be used to prevent stroke, both in primary and secondary stroke prevention (class 2a recommendation). We also review issues in folate metabolism that require further study, with regard to the form of folate to be used for stroke prevention. We recommend that the guideline be revised to say that B vitamins to lower homocysteine prevent stroke and that methylcobalamin or hydroxycobalamin should be used instead of cyanocobalamin.

Atrial fibrillation after closure of patent foramen ovale in the REDUCE clinical study.

OBJECTIVES: To describe the occurrence of postprocedural atrial fibrillation (AF) among patients with cryptogenic stroke undergoing patent foramen ovale (PFO) closure in the REDUCE clinical study and analyze for potential risk factors for the development of postprocedural AF. BACKGROUND: AF is an adverse event that might potentially counterbalance the stroke prevention benefit from PFO closure. Data on AF after transcatheter PFO closure are sparse. METHODS: We evaluated data from patients having PFO closure (Gore HELEX or Gore Cardioform Septal Occluder) in the REDUCE clinical trial (n = 408) in at post hoc explorative analysis. Median follow-up was 5.0 years. RESULTS: AF occurred in 30 patients (7.4%) after PFO closure with a total of 34 AF events. Most were reported as non-serious (68%), detected within 45 days post-procedure (79%), and resolved within 2 weeks of onset (63%). One subject with AF had recurrent stroke. Postprocedural AF occurred more frequently among subjects with higher age and large device sizes. Male sex was the only independent predictor of postprocedural AF. We found no association between the type of occluder (HELEX or Gore Cardioform Septal Occluder) or PFO anatomical characteristics and post-procedural AF. CONCLUSION: In the REDUCE clinical study, postprocedural atrial fibrillation was mostly early onset, transient and with no later recurrence. Postprocedural AF occurred more frequently among patients with higher age and larger devices. Male sex was the only independent predictor of postprocedural AF.

Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance.

AIMS: Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial. MATERIALS AND METHODS: Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study). RESULTS: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new-onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p = .002) and 0.74 (0.69, 0.94) for 45 mg/day. For new-onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p = .001) and 0.31 (0.59, 0.94; p = .001) respectively. For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata. CONCLUSIONS: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke.

Management of Patients with Embolic Stroke of Unknown Source: Interpreting the Evidence in the Light of Clinical Judgement.

PURPOSE OF REVIEW: To assess the validity of the belief that anticoagulation is not beneficial in patients with embolic stroke of unknown source (ESUS), and to asssess the benefits and safety of direct-acting oral anticoagulants (DOACs). RECENT FINDINGS: The failure of randomized trials to show benefit of anticoagulation in ESUS is probably due to misclassification of large artery atherosclerosis (LAA) as ESUS, as defined by a stenosis ≥ 50%. There are important differences among DOACs. There are a number of problems with dabigatran, and rivaroxaban and edoxaban are not suitable for once-daily dosing. Recent evidence from real-world practice indicates that apixaban is more effective and safer than rivaroxaban. Plaque burden should be included in the definition of LAA. Patients in whom a cardioembolic source is strongly suspected should be anticoagulated; antiplatelet agents are not significantly safer than DOACs, and are not effective in cardioembolic stroke.

Cerebrovascular Disease, Cardiovascular Disease, and Chronic Kidney Disease: Interplays and Influences.

PURPOSE OF REVIEW: We reviewed reasons for the high cardiovascular risk (CVD) of patients with chronic kidney disease (CKD), and explored alternatives to treatment of traditional risk factors to reduce CVD in CKD. RECENT FINDINGS: Besides traditional risk factors, patients with CKD are exposed to uremic toxins of two kinds: systemically derived toxins include asymmetric dimethylarginine (ADMA), total homocysteine (tHcy), thiocyanate, tumor necrosis factor alpha, and interleukin 6. Gut-derived uremic toxins (GDUT), products of the intestinal microbiome, include hippuric acid, indoxyl sulfate, p-cresyl sulfate, p-cresyl glucuronide, phenylacetylglutamine, and trimethylamine N-oxide (TMAO). Cyanocobalamin is toxic in patients with CKD. Approaches to reducing plasma levels of these uremic toxins would include diet to reduce GDUT, kidney transplantation, more intensive dialysis, and vitamin therapy to lower tHcy with methylcobalamin rather than cyanocobalamin. The high CVD risk in CKD requires consideration of therapies beyond treatment of traditional risk factors.

Secular trends of ischaemic heart disease, stroke, and dementia in high-income countries from 1990 to 2017: the Global Burden of Disease Study 2017.

BACKGROUND: We assessed secular trends in the burden of ischaemic heart disease (IHD), stroke, and dementia in the Organization for Economic Co-operation and Development (OECD) countries. METHODS: Using the Global Burden of Disease (GBD) Study 2017, we compared sex-specific and age-standardized rates of disability-adjusted life years (DALY); mortality, incidence, and prevalence of IHD and stroke; and dementia per 100,000 people, in the world, OECD countries, and Canada. RESULTS: From 1990 to 2017, the crude incidence number of IHD, stroke, and dementia increased 52%, 76%, and 113%, respectively. Likewise, the prevalence of IHD (75%), stroke (95%), and dementia (119%) increased worldwide. In addition during the study period, the crude global number of deaths of IHD increased 52%, stroke by 41%, and dementia by 146% (9, 6, and 3 million deaths in 2017, respectively). Despite an increase in the crude number of these diseases, the global age-standardized incidence rate of IHD, stroke, and dementia decreased by -27%, - 11%, and - 5%, respectively. Moreover, there was a decline in their age-standardized DALY rates (- 1.17%, - 1.32%, and - 0.23% per year, respectively) and death rates (- 1.29%, - 1.46%, and - 0.17% per year, respectively), with sharper downward trends in Canada and OECD countries. Almost all trends flattened during the last decade. CONCLUSIONS: From 1990 to 2017, the age-standardized burden of IHD, stroke, and dementia decreased, more prominently in OECD countries than the world. However, their rising crude numbers mainly due to population growth and ageing require urgent identification of reversible risk and protective factors.

Stroke Prevention: Little-Known and Neglected Aspects.

Combining available therapies has the potential to reduce the risk of stroke by 80% or more. A comprehensive review of all aspects of stroke prevention would be very lengthy; in this narrative review, we focus on some aspects of stroke prevention that are little-known and/or neglected. These include the following: (1) implementation of a Mediterranean diet; (2) B vitamins to lower homocysteine; (3) coordinated approaches to smoking cessation; (4) intensive lipid-lowering therapy; (5) lipid lowering in the elderly; (6) physiologically individualized therapy for hypertension based on renin/aldosterone phenotyping; (7) avoiding excessive blood pressure reduction in patients with stiff arteries; (8) treatment of insulin resistance with pioglitazone in stroke patients with prediabetes and diabetes; (9) impaired activation of clopidogrel in patients with variants of CYP2C19; (10) aspirin pseudoresistance due to enteric coating; (11) rationale for anticoagulation in patients with embolic stroke of unknown source; (12) pharmacologic properties of direct-acting oral anticoagulants that should be considered when choosing among them; (13) the identification of which patients with asymptomatic carotid stenosis are at a high enough risk to benefit from carotid endarterectomy or stenting; and (14) the importance of age in choosing between endarterectomy and stenting. Stroke prevention could be improved by better recognition of these issues and by implementation of the principles derived from them.

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials.

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Risk from low blood pressure in frail older adults: diastolic pressure and pulse pressure are important.

Blood pressure measurement with a cuff in patients with stiff arteries can be misleading, with false elevation of the diastolic pressure. Coronary flow, and most of the cerebral blood flow occur during diastole. There is a marked diastolic J curve in patients with diastolic pressure <60 mmHg and pulse pressure >60 mmHg. Aiming for a systolic target of 120 mmHg is not safe in some frail older patients.

Egg consumption associated with all-cause mortality in rural China: a 14-year follow-up study.

BACKGROUND: Dietary recommendations regarding egg intake remain controversial topic for public health. We hypothesized that there was a positive association between egg consumption and all-cause mortality. METHODS: To test this hypothesis, we enrolled 9885 adults from a community-based cohort in Anhui Province, China during 2003-05. Egg consumption was assessed by food questionnaire. Stratified analyses were performed for age, sex, body mass index (BMI), blood pressure, smoking, drinking and laboratory tests. RESULTS: After an average follow-up of 14.1 years, 9444 participants were included for analysis. A total of 814 deaths were recorded. Participants' BMI and lipid profile had no significantly difference between three egg consumption groups. BMI was 21.6±2.7 of the whole population, especially BMI>24 was only 17.3%. A bivariate association of egg consumption >6/week with increased all-cause mortality was observed compared with ≤6/week (RR: 1.35, 95% CI: 1.05, 1.73, P = 0.018). A significant interaction was observed for BMI ≥ 21.2 kg/m2 vs. BMI<21.2 kg/m2 (P for interaction: 0.001). No other significant interactions were found. CONCLUSIONS: In this study, consuming >6 eggs/week increased risk of all-cause mortality, even among lean participants, especially who with BMI ≥ 21.2 kg/m2. Eggs are an easily accessible and constitute an affordable food source in underdeveloped regions. Consuming <6 eggs/week may be the most suitable intake mode.

Reducing the Risk of Stroke in Patients with Impaired Renal Function: Nutritional Issues.

Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.

Measurement of carotid plaque burden.

PURPOSE OF REVIEW: To describe the uses of measurement of carotid plaque burden, as total plaque area (TPA), total plaque volume (TPV), and vessel wall volume (VWV), which includes plaque burden and wall volume. RECENT FINDINGS: Measurement of plaque burden is useful for risk stratification, research into the genetics and biology of atherosclerosis, for measuring effects of new therapies for atherosclerosis, and for treatment of high-risk patients with severe atherosclerosis. SUMMARY: Measurement of plaque burden is far superior to measurement of carotid intima-media thickness (IMT) in many ways, and should replace it. Vessel wall volume can be measured in persons with no plaque as an alternative to IMT.

Stroke Prevention: A Lifetime of Lessons.

In 44 years of practicing stroke prevention, I have learned many lessons; in this article, I hope to impart some of them. Three areas of my research are discussed. Controlling resistant hypertension is markedly improved by physiologically individualized therapy based on renin/aldosterone phenotyping; this is particularly important in black patients. Measurement of carotid plaque burden strongly predicts cardiovascular risk and is useful for genetic research and for a process called treating arteries instead of risk factors. Doing so in high-risk patients with asymptomatic carotid stenosis was associated with a >80% reduction in the 2-year risk of stroke and myocardial infarction. It also permitted the identification of extremes of atherosclerosis that are useful for studying both the genetics and the biology of atherosclerosis. Patients with very high plaque burden despite low levels of risk factors have an unexplained phenotype; those with little or no plaque despite high levels of risk factors are protected. Patients with unexplained atherosclerosis have higher plasma levels of toxic metabolites produced by the intestinal microbiome largely from egg yolk, red meat, and protein, and those metabolites are renally excreted. This has important dietary implications for stroke prevention. Lowering of plasma total homocysteine with B vitamins significantly reduces the risk of stroke. That was not apparent in early studies because harm from cyanocobalamin among participants with renal failure obscured the benefit among those with good renal function. We should be using B vitamins to prevent stroke but should use methylcobalamin or oxocobalamin instead of cyanocobalamin.

Stroke Prevention in Older Adults: Recent Advances.

The risks of stroke and dementia increase steeply with age, and both are preventable. At present, the best way to preserve cognitive function is to prevent stroke. Therapeutic nihilism based on age is common and unwarranted. We address recent advances in stroke prevention that could contribute greatly to prevention of stroke and dementia at a time when the aging of the population threatens to markedly increase the incidence of both. Issues discussed: (1) old patients benefit even more from lipid-lowering therapy than do younger patients; (2) patients with stiff arteries are at risk from a target systolic blood pressure <120 mm Hg; (3) the interaction of the intestinal microbiome, age, and renal function has important dietary implications for older adults; (4) anticoagulation with direct-acting oral anticoagulants should be prescribed more to old patients with atrial fibrillation; (5) B vitamins to lower homocysteine prevent stroke; and (6) most old patients in whom intervention is warranted for carotid stenosis would benefit more from endarterectomy than from stenting. An 80-year-old person has much to lose from a stroke and should not have effective therapy withheld on account of age. Lipid-lowering therapy, a more plant-based diet, appropriate anticoagulation or antiplatelet therapy, appropriate blood pressure control, B vitamins to lower homocysteine, and judicious intervention for carotid stenosis could do much to reduce the growing burden of stroke and dementia.

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke.

BACKGROUND: The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. METHODS: In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. RESULTS: We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P=0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure. CONCLUSIONS: Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894 .).

Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.

RATIONALE & OBJECTIVE: In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN: A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS: This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS: Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES: The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS: Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS: The analysis is post hoc and event rate is low. CONCLUSIONS: Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING: Government funding (National Key Research and Development Program of China).

ASSOCIATIONS BETWEEN ACCELERATED ATHEROSCLEROSIS, OXIDIZED LDL IMMUNE COMPLEXES, AND IN VITRO ENDOTHELIAL DYSFUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis. This study was designed to determine the association between atherosclerosis, oxidized LDL immune complexes (oxLDL-IC), and endothelial dysfunction in SLE. SLE patients were recruited, and carotid atherosclerotic total plaque area (TPA) was determined by ultrasound. Levels of oxLDL-IC were measured. In vitro endothelial function was measured by aortic endothelial nitric oxide (NO) production after culture of human aortic endothelial cells (HAEC) with SLE serum. Levels of oxLDL-IC are associated significantly with TPA. In vitro HAEC NO production after culture with SLE serum was positively correlated with serum complement. HAEC NO production was increased with sepiapterin to couple eNOS. To our knowledge, this is the first study to demonstrate an association between subclinical accelerated atherosclerosis and oxLDL-IC in SLE. This is also the first study to demonstrate the effect of sepiapterin on improving in vitro aortic endothelial cell function in SLE.