Chrysi Bogiatzi

Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis

OBJECTIVE To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS). DESIGN A prospective study. SETTING A teaching hospital. PATIENTS Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity. MAIN OUTCOME MEASURES We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003. RESULTS Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm(2) (SD, 96 mm(2)) to 23 mm(2) (SD, 86 mm(2)) (P < .001). CONCLUSIONS Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.

Secular Trends in Ischemic Stroke Subtypes and Stroke Risk Factors

Background and Purpose— Early diagnosis and treatment of a stroke improves patient outcomes, and knowledge of the cause of the initial event is crucial to identification of the appropriate therapy to maximally reduce risk of recurrence. Assumptions based on historical frequency of ischemic subtypes may need revision if stroke subtypes are changing as a result of recent changes in therapy, such as increased use of statins. Methods— We analyzed secular trends in stroke risk factors and ischemic stroke subtypes among patients with transient ischemic attack or minor or moderate stroke referred to an urgent transient ischemic attack clinic from 2002 to 2012. Results— There was a significant decline in low-density lipoprotein cholesterol and blood pressure, associated with a significant decline in large artery stroke and small vessel stroke. The proportion of cardioembolic stroke increased from 26% in 2002 to 56% in 2012 (P<0.05 for trend). Trends remained significant after adjusting for population change. Conclusions— With more intensive medical management in the community, a significant decrease in atherosclerotic risk factors was observed, with a significant decline in stroke/transient ischemic attack caused by large artery atherosclerosis and small vessel disease. As a result, cardioembolic stroke/transient ischemic attack has increased significantly. Our findings suggest that more intensive investigation for cardiac sources of embolism and greater use of anticoagulation may be warranted.

Recurrent Stroke and Patent Foramen Ovale A Systematic Review and Meta-Analysis

Background and Purpose— Recurrent cerebrovascular events are frequent in medically treated patients with patent foramen ovale (PFO), but it still remains unclear whether PFO is a causal or an incidental finding. Further uncertainty exists on whether the size of functional shunting could represent a potential risk factor. The aim of the present study was to evaluate if the presence of PFO is associated with an increased risk of recurrent stroke or transient ischemic attack and to investigate further if this relationship is related to the shunt size. Methods— We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of all available prospective studies reporting recurrent cerebrovascular events defined as cryptogenic stroke and transient ischemic attacks in medically treated patients with PFO diagnosed by echocardiography or transcranial sonography. Results— We identified 14 eligible studies including a total of 4251 patients. Patients with stroke with PFO did not have a higher risk of the combined outcome of recurrent stroke/transient ischemic attack (risk ratio=1.18; 95% confidence interval=0.78–1.79; P=0.43) or in the incidence of recurrent strokes (risk ratio =0.85; 95% confidence interval=0.59–1.22; P=0.37) in comparison with stroke patients without PFO. In addition, PFO size was not associated with the risk of recurrent stroke or transient ischemic attack. We also documented no evidence of heterogeneity across the included studies. Conclusions— Our findings indicate that medically treated patients with PFO do not have a higher risk for recurrent cryptogenic cerebrovascular events, compared with those without PFO. No relation between the degree of PFO and the risk of future cerebrovascular events was identified.

Identifying high-risk asymptomatic carotid stenosis.

INTRODUCTION With more intensive medical therapy, the risk of stroke in patients with asymptomatic carotid stenosis (ACS) is now below the risk of carotid endarterectomy or stenting (intervention); ∼ 90% of patients would be better with only medical therapy. It is important, therefore, to have methods to identify the ∼ 10% of patients who stand to benefit from intervention. AREAS COVERED We review the evidence that the risk of asymptomatic stenosis is now below the risk of intervention, and evidence for several approaches to identifying high-risk ACS: transcranial Doppler embolus detection, echolucency and neovascularity on ultrasound, ulceration on three-dimensional ultrasound, plaque composition on magnetic resonance imaging (MRI), plaque inflammation on positron emission tomography and assessment of cerebral blood flow reserve. EXPERT OPINION Carotid endarterectomy or stenting should be performed only in patients with ACS if they have microemboli on transcranial Doppler, three or more ulcers detected on three-dimensional ultrasound or other features of unstable plaque such as plaque echolucency on ultrasound, intraplaque hemorrhage detected on MRI, inflamed plaques detected on PET/CT or reduced cerebral blood flow reserve. Most patients with ACS (∼ 90%) would be better off with intensive medical therapy than with intervention.

Ezetimibe and Regression of Carotid Atherosclerosis Importance of Measuring Plaque Burden

Background and Purpose— There has been recent controversy over failure of ezetimibe to reduce carotid intima-media thickness. Much of this is based on failure to understand important differences among ultrasound phenotypes of atherosclerosis. Methods— We analyzed the effect of adding ezetimibe to the regimen of patients being followed in vascular prevention clinics where measurement of carotid plaque burden (total plaque area) is used to guide therapy. Results— There were complete data in 231 patients with total plaque area for 2 years before and 2 years after initiation of ezetimibe. In the 2 years before and after initiation of ezetimibe, total cholesterol decreased significantly before (P<0.0001) and after initiation of ezetimibe (P<0.0001); low-density lipoprotein cholesterol declined significantly before (P<0.0001) and after (P=0.003) initiation of ezetimibe. Triglycerides declined significantly before ezetimibe (P<0.0001) but did not change after addition of ezetimibe (P=0.48). High-density lipoprotein cholesterol did not change significantly before (P=0.87) but declined significantly after ezetimibe (P=0.03). Despite the decline in low-density lipoprotein cholesterol before addition of ezetimibe, there was a significant mean increase in within-individual total plaque area in the 2 years before addition of ezetimibe by 6.89±39.57 mm2 (SD); after addition of ezetimibe, despite the decline in high-density lipoprotein, plaque area decreased by −3.05±SD 38.18 mm2 SD (P<0.01). Conclusions— Ezetimibe appears to regress carotid plaque burden. To assess effects of antiatherosclerotic therapies, it is important to measure plaque burden. These findings should be tested in a clinical trial.

Risk of Stroke at the Time of Carotid Occlusion

IMPORTANCE Many patients with asymptomatic carotid stenosis are offered carotid stenting for the prevention of carotid occlusion. However, this treatment may be inappropriate if the risk of stroke is low at the time of occlusion and with intensive medical therapy. OBJECTIVES To determine the risk resulting from progression to occlusion among patients with asymptomatic carotid stenosis and to assess the role of severity of carotid stenosis or the presence of contralateral occlusion as factors that may predict the risk of stroke or death after occlusion of a previously asymptomatic carotid stenosis. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective analysis of data collected from patients at the Stroke Prevention Clinic of Victoria Hospital from January 1, 1990 (when annual surveillance with carotid ultrasonography first began), through December 31, 1995, or the Stroke Prevention at University Hospital from January 1, 1995, through December 31, 2012. The last date of follow-up was August 26, 2014. EXPOSURES A new carotid occlusion during annual monitoring with carotid duplex ultrasonography (index occlusion). MAIN OUTCOMES AND MEASURES Ipsilateral stroke or transient ischemic attack, death from ipsilateral stroke, or death from unknown cause. RESULTS Among 3681 patients in our clinic database with data on sequential annual carotid ultrasonographic examinations during the study period, 316 (8.6%) were asymptomatic before an index occlusion that occurred during observation. Most of the new occlusions (254 of 316 [80.4%]) occurred before 2002, when medical therapy was less intensive; the frequency decreased by quartile of years (P < .001, χ2 test). Only 1 patient (0.3%) had a stroke at the time of the occlusion, and only 3 patients (0.9%) had an ipsilateral stroke during follow-up (all before 2005). In Kaplan-Meier survival analyses, neither severity of stenosis (P = .80, log-rank test) nor contralateral occlusion (P = .73) predicted the risk of ipsilateral stroke or transient ischemic attack, death from stroke, or death from unknown cause at a mean (SD) follow-up of 2.56 (3.64) years. In Cox proportional hazards regression analyses, only age (P = .02), sex (P = .01), and carotid plaque burden (P = .006) significantly predicted risk of those events. CONCLUSIONS AND RELEVANCE The risk of progression to carotid occlusion is well below the risk of carotid stenting or endarterectomy and has decreased markedly with more intensive medical therapy. Preventing carotid occlusion may not be a valid indication for stenting.

Metabolic products of the intestinal microbiome and extremes of atherosclerosis

BACKGROUND AND AIMS There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area. METHODS Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <-2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure - gut-derived uremic toxins (GDUT) - were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden. CONCLUSIONS The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function

Metabolic products of the intestinal microbiome such as trimethylamine N-oxide (TMAO) that accumulate in renal failure (gut-derived uremic toxins, GDUTs) affect atherosclerosis and increase cardiovascular risk. We hypothesized that patients on a Mediterranean diet and those consuming lower amounts of dietary precursors would have lower levels of GDUTs. Patients attending vascular prevention clinics completed a Harvard Food Frequency Questionnaire (FFQ) and had plasma levels of TMAO, p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresyl glucuronide, phenyl acetyl glutamine, and phenyl sulfate measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Carotid plaque burden was measured by ultrasound; CKD-Epi equations were used to estimate the glomerular filtration rate. In total, 276 patients completed the study. Even moderate renal function significantly increased plasma GDUTs, which were significantly associated with higher carotid plaque burden. There was no significant difference in plasma levels of any GDUT associated with a Mediterranean diet score or with intake of dietary precursors. In omnivorous patients with vascular disease, the intake of dietary precursors of intestinal metabolites or adherence to a Mediterranean diet did not change plasma GDUT. Approaches other than diet, such as probiotics and repopulation of the intestinal microbiome, may be required to mitigate the adverse effects of GDUTs.

Data on the gut and saliva microbiota from a cohort of atherosclerosis patients determined by 16S rRNA gene sequencing

This work was conducted to characterize the 16S rRNA gene profile of a cohort of patients with traditional risk factors for developing atherosclerosis. The patients in the cohort were divided into two extremes; those predicted to develop extreme atherosclerosis who did not (Protected), and those predicted not to develop atherosclerosis who did (Unexplained). Bacterial DNA was isolated from stool and saliva and this was used to determine the V4 variable region of the 16S rRNA gene sequence composition of the samples in triplicate.

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.