Why do guidelines recommend screening for abdominal aortic aneurysms, but not for asymptomatic carotid stenosis? A plea for a randomized controlled trial.

BACKGROUND: Current guidelines do not recommend screening for asymptomatic carotid artery stenosis (AsxCS). The rationale behind this recommendation is that detection of AsxCS may lead to an unnecessary carotid intervention. In contrast, screening for abdominal aortic aneurysms is strongly recommended. METHODS: A critical analysis of the literature was performed to evaluate the implications of detecting AsxCS. RESULTS: Patients with AsxCS are at high risk for future stroke, myocardial infarction and vascular death. Population-wide screening for AsxCS should not be recommended. Additionally, screening of high-risk individuals for AsxCS with the purpose of identifying candidates for a carotid intervention is inappropriate. Instead, selective screening for AsxCS should be considered and should be viewed as an opportunity to identify individuals at high risk for atherosclerotic cardiovascular disease and future cardiovascular events for the timely initiation of intensive medical therapy and risk factor modification. CONCLUSIONS: Although mass screening should not be recommended, there are several arguments suggesting that selective screening for AsxCS should be considered. The rationale supporting such selective screening is to optimize risk factor control and to initiate intensive medical therapy for prevention of future cardiovascular events, rather than to identify candidates for an intervention.

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.

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.

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.

Management of asymptomatic carotid stenosis.

Patients with asymptomatic carotid stenosis (ACS) are at very high risk of coronary events, so they should all receive intensive medical therapy. What is often accepted as "best medical therapy" is usually suboptimal. Truly intensive medical therapy includes lifestyle modification, particularly smoking cessation and a Mediterranean diet. All patients with ACS should receive intensive lipid-lowering therapy, should have their blood pressure well controlled, and should receive B vitamins for lowering of plasma total homocysteine (tHcy) if levels are high; a commonly missed cause of elevated tHcy is metabolic B12 deficiency, which should be diagnosed and treated. Most patients with ACS would be better treated with intensive medical therapy than with either carotid endarterectomy (CEA) or stenting (CAS). A process called "treating arteries instead of treating risk factors" markedly reduced the risk of ACS in an observational study; a randomized trial vs. usual care should be carried out. The few patients with ACS who could benefit (~15%, or perhaps more if recent evidence regarding the risk of intraplaque hemorrhage is borne out) can be identified by a number of features. These include microemboli on transcranial Doppler, intraplaque hemorrhage, reduced cerebrovascular reserve, and echolucency of plaques, particularly "juxtaluminal black plaque". No patient should be subjected to CAS or CEA without evidence of high-risk features, because in most cases the 1-year risk of stroke or death with intervention is higher with either CEA (~2%) or CAS (~4%) than with intensive medical therapy (~0.5%). Most patients, particularly the elderly, would be better treated with CEA than CAS. Most strokes can be prevented in patients with ACS, but truly intensive medical therapy is required.

Uses of ultrasound in stroke prevention.

Ultrasound methods are useful in stroke prevention in several ways. Measurement of carotid plaque burden, as either total plaque area (TPA) or total plaque volume (TPV) are strong predictors of cardiovascular risk: much stronger than intima-media thickness, which does not represent true atherosclerosis, but a biologically and genetically distinct phenotype. Measurement of plaque burden is also useful for the study of genetics, and of new risk factors such as toxic products of the intestinal microbiome. Carotid plaque burden is highly correlated with and as predictive of risk as coronary calcium scores, but is less costly and does not require radiation. Furthermore, because carotid plaques change in time over a period of months, they can be used for a new approach to vascular prevention: "Treating arteries instead of treating risk factors". In high-risk patients with asymptomatic carotid stenosis (ACS), this approach, implemented in 2003 in our clinics, was associated with a >80% reduction of stroke and myocardial infarction over 2 years. "Treating arteries without measuring plaque would be like treating hypertension without measuring blood pressure". Ultrasound methods can also be used to assess plaque vulnerability, by detecting echolucency, ulceration and plaque inhomogeneity on assessment of plaque texture. Transcranial Doppler (TCD) embolus detection is useful for risk stratification in patients with ACS; patients with two or more microemboli in an hour of monitoring have a 1-year risk of 15.6%, vs. 1% without microemboli, so this very clearly distinguishes which patients with ACS could benefit from intervention. TCD saline studies are more sensitive than trans-esophageal echocardiography for detection of patent foramen ovale, and more predictive of recurrent stroke. These methods should be more widely used, to reduce the increasing burden of stroke in our aging populations.

Traffic-Related Air Pollution and Carotid Plaque Burden in a Canadian City With Low-Level Ambient Pollution.

Background The association between fine particulate matter and cardiovascular disease has been convincingly demonstrated. The role of traffic-related air pollutants is less clear. To better understand the role of traffic-related air pollutants in cardiovascular disease development, we examined associations between NO2, carotid atherosclerotic plaque, and cardiometabolic disorders associated with cardiovascular disease. Methods and Results Cross-sectional analyses were conducted among 2227 patients (62.9±13.8 years; 49.5% women) from the Stroke Prevention and Atherosclerosis Research Centre (SPARC) in London, Ontario, Canada. Total carotid plaque area measured by ultrasound, cardiometabolic disorders, and residential locations were provided by SPARC medical records. Long-term outdoor residential NO2 concentrations were generated by a land use regression model. Associations between NO2, total carotid plaque area, and cardiometabolic disorders were examined using multiple regression models adjusted for age, sex, smoking, and socioeconomic status. Mean NO2 was 5.4±1.6 ppb in London, Ontario. NO2 was associated with a significant increase in plaque (3.4 mm2 total carotid plaque area per 1 ppb NO2), exhibiting a linear dose-response. NO2 was also positively associated with triglycerides, total cholesterol, and the ratio of low- to high-density lipoprotein cholesterol (P<0.05). Diabetes mellitus mediated the relationship between NO2 and total carotid plaque area (P<0.05). Conclusions Our results demonstrate that even low levels of traffic-related air pollutants are linked to atherosclerotic plaque burden, an association that may be partially attributable to pollution-induced diabetes mellitus. Our findings suggest that reducing ambient concentrations in cities with NO2 below current standards would result in additional health benefits. Given the billions of people exposed to traffic emissions, our study supports the global public health significance of reducing air pollution.

Rationale for screening selected patients for asymptomatic carotid artery stenosis.

Stroke is a leading cause of death and disability worldwide. Approximately 15% of all first-ever strokes occur due to atheroembolism from a previously undetected/untreated asymptomatic carotid stenosis (ACS). Despite that, international guidelines do not recommend screening for ACS. The rationale for not recommending screening include: (a) the harm associated with screening, (b) the questionable clinical benefit associated with surgery, (c) the lack of proven reduction in the risk of stroke, (d) the large number of false positive/false negative tests, and (e) the cost-effectiveness of such screening programs. A critical analysis of each of these arguments is presented. Patients with ACS have a very high risk of all-cause and cardiac mortality. Detection of ACS should not be viewed as an indication for surgery, but rather as an opportunity to implement best medical treatment (BMT) and lifestyle changes to prevent not only strokes, but also cardiac events. The implementation of screening programs for abdominal aortic aneurysms (AAAs) has led to a considerable reduction in the number of ruptured AAAs and AAA-related deaths. Similarly, screening high-risk individuals for ACS would enable timely identification of patients with ACS and implementation of BMT and lifestyle measures to prevent future strokes and cardiac events.

Increased carotid plaque burden in patients with family medical history of premature cardiovascular events in the absence of classical risk factors.

INTRODUCTION: The hypothesis that relates atherosclerosis to traditional risk factors (TRF) seems to be not as adequate as previously thought; other risk factors (RF) need to be considered to prevent atherosclerosis progression. Although a family medical history of premature cardiovascular events (FHx) has been considered the putative RF for decades, it has not been incorporated routinely into cardiovascular risk evaluation along with another RF. The objective of this study was to investigate whether FHx is associated with a higher atherosclerotic burden, measured as carotid total plaque area (TPA) in a population having no traditional RF. MATERIAL AND METHODS: The study included 4,351 primary care patients in Argentina. After excluding a personal history of cardiovascular disease (CVD) and TRF: hypertension, diabetes mellitus, hypercholesterolemia, smoking history, and body mass index (BMI) > 25 kg/cm2, 34 patients with FHx were identified. Compared to 56 matched controls TPA was 86% higher in FHx patients (p < 0.05). A second analysis performed in hypertensive patients but no other TRF; 32 patients with FHx were identified. RESULTS: Compared with 44 matched controls, TPA was 77% higher in FHx patients (p < 0.05). A final analysis using a generalized linear model with TPA progression as the response variable suggests that TPA progresses more rapidly in FHx patients compared to controls. CONCLUSIONS: The FHx was associated with increased TPA burden and progression in the absence of other TRF. This supports ultrasound screening in FHx patients in order to detect high-risk patients who may benefit from early intervention.

Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial.

Importance: In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. Objective: To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. Design, Setting, and Participants: The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Interventions: Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. Main Outcomes and Measures: The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Results: Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Conclusions and Relevance: Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. Trial Registration: ClinicalTrials.gov identifier: NCT00091949.

Moderate Renal Impairment and Toxic Metabolites Produced by the Intestinal Microbiome: Dietary Implications.

OBJECTIVE: Toxic metabolites produced by the intestinal microbiome from animal proteins, carnitine (mainly from red meat), or phosphatidylcholine (mainly from egg yolk), have important adverse effects on cardiovascular disease. These are renally eliminated and may be termed gut-derived uremic toxins (GDUT). We hypothesized that even moderate renal impairment and intake of nutrient precursors would raise plasma levels of GDUT. DESIGN: A cohort study. SETTING: Academic medical center. SUBJECTS: Patients attending stroke prevention clinics at a university medical center were recruited. MAIN OUTCOME MEASURE: Nutrient intake was assessed by the 131-item Harvard Food Frequency Questionnaire; estimated glomerular filtration rate (eGFR) was caculated using the Chronic Kidney Disease-Epidemiology (EPI) equations. Plasma levels of trimethylamine n-oxide, p-cresyl sulfate, hippuric acid, p-cresyl glucuronide, pheny acetyl glutamine, and phenyl sulfate were measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Among 316 patients recruited, the mean (standard deviation [SD]) age was 66.74 (10.42) years; 59.7% were men. Mean eGFR was 76.03 ± 20.01; 57 (18%) had eGFR<60 mL/min/1.73 m2. Plasma levels of all GDUT were significantly higher even with moderate reduction of eGFR. Nutrient intake affected plasma levels of some GDUT; the effects differed by eGFR above and below 60 mL/min/1.73 m2. Plasma levels were obtained fasting, so we probably underestimated the effect of nutrient intake. CONCLUSIONS: Even moderate impairment of renal function was associated with higher plasma levels of GDUT. This has dietary implications for patients at risk of atherosclerosis, particularly in those with impaired renal function (including the elderly): they should limit intake of animal protein, red meat, and egg yolk. It also points the way to novel approaches to vascular prevention, including more intensive dialysis, renal transplantation, and modification of the intestinal microbiome with probiotics or fecal transplantation.

Smoking cessation and outcome after ischemic stroke or TIA.

OBJECTIVE: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. METHODS: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. RESULTS: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). CONCLUSION: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Transcranial Doppler monitoring for microemboli: a marker of a high-risk carotid plaque.

In the United States, 90% of carotid intervention is being performed for asymptomatic carotid stenosis, even though 90% of patients would be better treated with intensive medical therapy. This is being justified by comparing risks of stroke or death with medical therapy during clinical trials completed decades ago (approximately 2% per year) with risks of intervention with carotid artery stenting (CAS) versus carotid endarterectomy in recent trials that did not have a medical arm. Such extrapolations are, simply put, invalid. Even though the two most recent papers comparing carotid endarterectomy with CAS reported that the long-term risk (after first deducting periprocedural risks) is similar to that with medical therapy (approximately 0.5% per year), when the periprocedural risks are considered (approximately 3% with stenting v 1.5% with CAS), most patients would be better treated with intensive medical therapy. Furthermore, it must be recognized that the low risks observed in clinical trials with highly selected surgeons and interventionalists are much lower than in real-world practice. It is therefore necessary to have ways to identify, among patients with asymptomatic carotid stenosis, the few (approximately 10% to 15%) who could benefit from intervention. Indicators of vulnerable plaque, such as ulceration, juxtaluminal lucent plaque, intraplaque hemorrhage on magnetic resonance imaging, and plaque inflammation on positron emission tomography/computed tomography are in development for that purpose. The best-validated approach is detection of microemboli on transcranial Doppler. A prospective single-center study of 468 patients showed that microemboli identified high-risk asymptomatic stenosis; this was validated by a prospective multicenter international study in 467 patients. Increased risk with microemboli persisted in the era of lower risks with intensive medical therapy. Patients with asymptomatic carotid stenosis should not be offered CAS or carotid endarterectomy without first being identified as high risk; percent stenosis does not do so. Currently, the best way to improve the risk to benefit ratio for intervention is transcranial Doppler embolus detection.

Association of homocysteine and smoking with cerebral microemboli in patients with mechanical heart valves: a transcranial Doppler study.

Objectives: Microembolic signals (MES) on transcranial Doppler (TCD) predict stroke and cognitive decline. Plasma levels of total homocysteine (tHcy), a prothrombotic factor, are higher in patients with microemboli in carotid stenosis and in patients with paradoxical embolism. In this study we assessed the association between the level of tHcy and the number of MES in patients with mechanical heart valves (MHVs). Methods: TCD monitoring was performed to detect MES before and after breathing 100% oxygen and repeated every 2-4 weeks up to six times. Results: Twenty-five patients with MHVs (mean age: 63.60±10.15 years) participated in this study; 15 were men (66.47±7.25 years) and 10 were women (59.30±12.60 years). In total, there were 126 study visits. In multiple regression, higher tHcy was associated with more MES in both preoxygenation (OR 1.34 (95% CI 1.07 to 1.68, P=0.009)) and postoxygenation (OR 1.40 (95% CI 1.07 to 1.83, P=0.01)) phases. Current smoking and the length of time between the operation and monitoring also correlated with a higher number of MES before and after breathing oxygen, particularly in women. Conclusions: Higher tHcy and smoking were associated with a higher MES count in both preoxygenation and postoxygenation phases. Because smoking can be stopped and hyperhomocysteinaemia is treatable, these are clinically important findings.