Emile R. Mohler

Stroke After Aortic Valve Surgery Results From a Prospective Cohort

Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized.nnMethods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P =0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P =0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay.nnConclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.nn# CLINICAL PERSPECTIVE {#article-title-47}

The Pathogenesis and Treatment of the Valvulopathy of Aortic Stenosis: Beyond the SEAS

Fibrocalcific aortic stenosis (AS) results from an active process similar to atherosclerosis that involves basement membrane disruption, lipid deposition, inflammatory cell infiltration, and calcification. Consequently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been extensively studied as potential therapeutic agents capable of slowing the progression of AS. However, two randomized trials, SALTIRE and the SEAS study, showed no benefit with statin therapy for AS. These results have shed doubt over the efficacy of statin therapy for AS, although their potential efficacy at early stages of aortic valve disease remains possible. In this article, we review the pathophysiology of fibrocalcific AS and discuss future directions for its nonsurgical management in the post-SEAS era.

The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG- PET trial

OBJECTIVESnThis study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques.nnnMETHODSnSubjects with documented atherosclerosis (nxa0=xa072) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100xa0mg once daily), placebo, or atorvastatin (80xa0mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBRxa0≥xa01.6) at the baseline).nnnRESULTSnTreatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], pxa0=xa00.34; ΔTBR AS: -0.01 [-0.31, 0.28], pxa0=xa00.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], pxa0=xa00.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], pxa0=xa00.04) and arterial inflammation in active slices (ΔTBRASxa0=xa0-0.24 [95% CI: -0.46, -0.01], pxa0=xa00.04).nnnCONCLUSIONSnThe findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation.

Atherosclerotic Plaque Inflammation Varies Between Vascular Sites and Correlates With Response to Inhibition of Lipoprotein‐Associated Phospholipase A2

Background Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site‐specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs). Methods and Results Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site‐specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein‐associated phospholipase A2 (Lp‐PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp‐PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site‐specific differences in plaque severity. In the AAs, normalized plaque area was 4.4‐fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5‐fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib‐induced attenuation of normalized plaque area was site‐specific, as CORs responded 2.9‐fold more than AAs (P=0.045). Conclusions While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp‐PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti‐inflammatory therapeutics.

Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA2 in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA2. Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA2 reduces plasma Lp-PLA2 activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA2 inhibitors.

Analysis of femoral artery intima-media thickness during the cardiac cycle

BACKGROUNDnVariations in the intima-media thickness (IMT) of the carotid artery during the cardiac cycle are well established. The change in femoral IMT during the cardiac cycle is largely unknown. This study focuses on the variation of femoral IMT, vessel diameter, and cross-sectional area (CSA) of the IMT during the cardiac cycle.nnnMETHODSnVideo clips of the femoral artery were obtained using B-mode ultrasonography in 60 patients between the ages of 18 and 50. IMT and diameter measurements were made using automated software, and CSA was subsequently calculated. Triplicate measurements of each femoral artery were made at three points in the cardiac cycle: the R wave, the T wave, and at the point of maximal vessel diameter falling after the T wave and before the following P wave.nnnRESULTSnFemoral IMT, diameter, and CSA did not show a statistically significant difference with measurement on the R versus the T wave (P>0.36, P>0.28, and P>0.76, respectively). Interestingly, when comparing measurements on the R or T wave with measurements taken at the maximum vessel diameter, there was a statistically significant difference in vessel diameter (P<0.001) and CSA (P<0.005) but not in femoral IMT (P>0.2).nnnCONCLUSIONSnUnlike studies of the carotid artery, there were no statistically significant differences between measurements made at the R versus the T wave. There were, however, statistically significant differences noted in diameter and CSA when measurements were taken at a point later in the cardiac cycle. This has ramifications for future studies on vascular remodeling.

The Role of Femoral Artery Ultrasound Measurements in Predicting Restenosis following Endovascular Intervention

Background Although endovascular interventions for peripheral artery disease (PAD) have become increasingly common, they are associated with a significant rate of restenosis. An improved understanding of the risk factors for restenosis is needed to guide the management of patients with PAD. Methods We performed a cross-sectional analysis of 101 patients with PAD, to determine the association between clinical predictors, novel imaging measures of vascular function of the femoral artery [intima-media thickness, diameter, and intima-media cross-sectional area, change in diameter (delta diameter), average expansion and average contraction], and risk of reintervention. Univariable and multivariable associations between clinical and imaging measures and the need for reintervention were assessed using logistic regression. The predictive accuracy of the selected regression model and added predictive value of imaging measures were assessed using the area under the Receiver operating characteristic curve (AUC). The added predictive value of ultrasound was assessed by comparing AUC of the selected model with clinical parameters alone with that of the same model with additional ultrasound parameters. Results Of the 101 patients with PAD, 20 underwent recent multiple reinterventions. Vessel diameter was statistically significantly smaller in the group who underwent multiple reinterventions, p = 0.0170. Univariate logistic regression revealed that smoking status, hypertension, hypercholesterolemia, and chronic renal insufficiency were clinical parameters that met the statistical cut point of p ≤ 0.20. In the multivariable model, chronic renal insufficiency status (odds ratio (OR) = 8.27, 1.17–58.25), hypertension (OR = 0.145, 0.020–1.062), and femoral artery diameter (OR = 0.375, 0.136–1.031) remained important predictors for reintervention. The AUC for the clinical multivariable logistic regression model was 0.7481 while that for the model additionally including the ultrasound parameters was 0.8325 (p = 0.044). Conclusions Including ultrasound parameters in the risk prediction model for restenosis improved the ability to predict restenosis in this group of patients with known PAD. Further study is needed to define its utility in preoperative assessment and risk stratification before revascularization.

Progression of Peripheral Artery Disease to Critical Limb Ischemia

Critical limb ischemia (CLI), often considered the end stage of peripheral artery disease (PAD), is a tipping point in the balance between metabolic supply and demand of the lower extremity. This balance hinges on many factors, and the progression from stable PAD to CLI depends on the complex interplay of these variables. Despite the fact that PAD is classically categorized by disease severity, the natural history of PAD progression and general development of CLI does not follow a strictly linear path, a fact characterized by the often insidious clinical presentation of CLI. From a pathophysiologic perspective, CLI is the final result of the common atherogenic pathway that causes PAD. However, CLI manifests only in selected case largely due to a loss of compensatory mechanisms that leads to overt tissue ischemia. Many of the risk factors that contribute to the development of PAD are also responsible for its progression and ultimately for development of CLI, and important information can be gleaned from their modification both in PAD and CLI.

A Cross-Sectional Analysis of Femoral Artery Intima-Media Thickness

Introduction. —Arterial intima thickness (IMT) of the carotid artery has been established as a surrogate marker of atherosclerosis. The role of femoral IMT remains incompletely defined. This study was undertaken to define the potential relationship between patient demographics, comorbidities, and femoral IMT and to establish it as a potential marker for future peripheral arterial disease. Methods. —A total of 160 patients (89 male, 71 female) between the ages of 18 and 50 years were enrolled and demographic data were obtained by chart review. Images of the common femoral artery were obtained with B-mode ultrasonography gated to the R-wave of the electrocardiograph. Automated edge detection software (Carotid Analyzer for Research) was used to measure femoral IMT and vessel diameter, and these measurements were used to derive the IMT cross-sectional area (CSA). Triplicate measurements of each femoral artery were made and averaged. T-tests and multivariate analysis were performed and significance was indicated by a p < 0.05. Results. —The mean femoral IMT measurements for men and women were 0.514 ± 0.011 mm and 0.465 ± 0.005 mm, respectively. Univariate analysis found significant differences in IMT for sex, age, and presence of diabetes, hypercholesterolemia, and hypertension. Univariate analysis found significant differences in CSA for sex, age, race, body mass index (BMI), and presence of chronic renal insufficiency and hypercholesterolemia. When significant variables were included in a multivariate regression, age and sex (p < 0.001) remained significant predictors of IMT and age, sex, and BMI (p < 0.001) remained significant predictors of CSA. Conclusions. —In this subset of patients, multivariate analysis revealed a thicker IMT in males and in patients ≥35 years of age. Greater IMT CSA was associated with male sex, age ≥ 35 and BMI ≥ 30. These findings have ramifications for the future study of femoral IMT as it relates to atherosclerosis and vessel remodeling.

Carotid Intima-Media Thickness and Plaque Morphology in Carotid Stent Patients over Time

Introduction Carotid intima-media thickness (CIMT) is a well-known correlate of atherosclerotic disease. CIMT has not been studied in patients who have undergone carotid artery stenting. We sought to determine the effects of carotid artery stenting on common carotid artery (CCA) CIMT as well as carotid plaque morphology over time. Methods This was a retrospective chart review of 20 patients at the investigating institution. Demographic and clinical data were recorded. Gray scale B-mode images were used to perform measurements of CCA CIMT at three different locations in the stented as well as nonstented CCA by two independent observers. Mean values were calculated, and the CIMT of the stented side was compared with its control at each time point. Studies were performed preoperatively, at 1 month, 3 months, 6 months, 12 months, and 24 months postoperatively. Characterization of plaque morphology was also made at each time point. Results There were 7 female and 13 male participants. CIMT initially decreased on the stented side at 3 months but showed an increase during a 24-month period that was statistically different from the control group (p > 0.031). Female participants demonstrated a smaller CIMT at each time point compared with male participants with a relatively stable CIMT whereas male participants demonstrated an increase in CIMT over time. A history of diabetes, smoking, statin use, or angiotensin-converting enzyme inhibitor use did not appear to affect CIMT. Characterization of carotid plaque morphology demonstrated that the majority of plaques were heterogeneous in nature and became more homogeneous after stenting. Conclusions CIMT of the CCA increases after carotid stenting. Interestingly, female participants exhibit a smaller CIMT that is not subject to change over time. The majority of plaques was heterogeneous in nature and became more stable over time. These findings lend insight into patterns of vessel wall healing after angioplasty and stenting.