Nardi, Valentina

Abstract Background A higher serum phosphorus level, although within the normal range has been linked to coronary artery and aortic calcification in the non-transplant population. Coronary calcification is mostly associated with donor-derived lesions, and is uncommon within the first years after heart transplantation. Purpose We aimed to investigate the association of phosphorus levels with plaque calcification after heart transplantation. Methods A total of 156 patients who underwent virtual histology intravascular ultrasound (VH-IVUS) studies for cardiac allograft vasculopathy (CAV) surveillance and had fasting serum phosphorus levels <4.5 mg/dL, were included in the analyses. IVUS analyses were performed in the proximal left anterior descending artery, and plaque composition of dense calcium (DC) was evaluated using VH-IVUS, and presented as percent DC of total plaque volume. The patients were separated into 3 groups according to tertiles of serum phosphorus levels. Results Mean recipient and donor ages were 54±13 and 31±14 years, respectively. Mean serum phosphorus in recipients was 3.5±0.6 mg/dL, with median time after transplantation at the IVUS studies of 6 (3,10) years. There were no significant differences in %DC between phosphorus tertiles in patients who underwent IVUS within 6 years after transplantation (p=0.11, Fig. 1A). However, beyond 6 years after transplantation, we observed an incremental association between phosphorus levels and the extent of calcification (p=0.02, Fig. 1B). In this group, serum phosphorus levels significantly correlated with %DC (standardized β=0.29, P=0.008), and this correlation remained significant after adjustment for donor age, recipient age, and eGFR (standardized β=0.26, P=0.001). Conclusion Higher serum phosphorus levels were associated with a level-dependent increase in calcified coronary artery plaque in patients starting 6 years post heart transplant. Long-term exposure to higher serum phosphorus, even within the normal range, might promote plaque calcification after heart transplantation. Funding Acknowledgement Type of funding sources: None.

Background White matter hyperintensity (WMH), characterized by hyperintensities on T2‐weighted fluid‐attenuated inversion recovery brain magnetic resonance imaging, has been linked to an increased risk of ischemic stroke (IS). Endothelial dysfunction is an indicator of vascular dysfunction, predicting the risk of IS. This study aimed to investigate the association between endothelial dysfunction and regional WMH, and its impact on future risk of IS. Methods and Results We enrolled 219 patients (mean age, 53.1±14.1 years; 34.7% men) who underwent peripheral endothelial function assessment using reactive hyperemia peripheral arterial tonometry and brain magnetic resonance imaging without any history of IS. Volumetric WMH segmentation was automatically extrapolated using a validated automated digital tool. Total and juxtacortical WMH volume/intracranial volume (%) increased with aging and became more prominent in patients aged >50 years (n=131) than those aged ≤50 years (n=88) (total WMH: ≤50 years, Pearson r =0.24, P =0.03; >50 years, Pearson r =0.62, P <0.0001; juxtacortical WMH: ≤50 years, Pearson r =0.09, P =0.40; >50 years, Pearson r =0.55, P <0.0001). Reactive hyperemia peripheral arterial tonometry index was negatively associated with total and juxtacortical WMH volume/intracranial volume (%) in patients aged >50 years after adjustment for other covariates (reactive hyperemia peripheral arterial tonometry index, standardized β coefficient −0.17, P =0.04). Juxtacortical WMH volume/intracranial volume (%) was associated with an increased risk of IS during median follow‐up of 6.5 years (hazard ratio, 1.47; 95% CI, 1.05–1.92; P =0.03). Conclusions Peripheral endothelial dysfunction is associated with an increased volume of juxtacortical WMH in patients aged >50 years, which is a potential marker to predict future risk of IS.

Background Little is known about the impact that cardiovascular (CV) risk factors have on the formation of various carotid atherosclerotic plaque features. This study set out to assess the association between CV risk factors and plaque characteristics on computed tomography (CT) angiography (CTA). Materials and methods A retrospective review was completed of consecutive patients that underwent a carotid endarterectomy and had CTA imaging of the head and neck vasculature. Atherosclerotic plaques of both carotid arteries were evaluated for calcification(s), low-density plaque (LDP) components, ulceration(s), and degree of stenosis. Various clinical CV risk factors were assessed using medical records. Last recorded laboratory levels were dichotomized into categories: total cholesterol <200 or ≥200 mg/dL, low-density lipoprotein (LDL) <130 or ≥130 mg/dL, high-density lipoprotein <35 or ≥35 mg/dL, and triglyceride <200 or ≥200 mg/dL. Results Of 97 included patients, 62 were male (63.9%); the average age was 72.7 (standard deviation = 9.5). Calcifications were in 95/97 (97.9%) of patients (one or both carotid plaques); LDP components were in 73/97 (75.3%), and ulcerations were in 21/97 (21.6%). Elevated total cholesterol and elevated LDL levels were both associated with a higher likelihood of LDP components ( p = 0.004 and p = 0.02, respectively). There were no other statistically significant associations between individual plaque features or severity of arterial stenosis and CV risk factors. Conclusion In carotid atherosclerotic plaques, LDP components are more frequently present in one or both carotid arteries in patients with elevated total cholesterol and/or LDL levels. Such findings raise the possibility that cholesterol levels may be directly related to the formation of specific high-risk plaque features.

Background Using computed tomography angiography to differentiate between components of carotid atherosclerotic lesions remains largely elusive. This study sought to validate a semi-automated software for computed tomography angiography plaque analysis using histologic comparisons. Materials and Methods A retrospective review was performed of consecutive patients that underwent a carotid endarterectomy, with pre-procedural computed tomography angiography imaging of the cervical arterial vasculature available for review. Images were evaluated using a commercially-available software package, which produced segmented analyses of intraplaque components (e.g. intraplaque hemorrhage, lipid-rich necrotic core, and calcifications). On imaging, each component was assessed in terms of its (1) presence or absence, and (2) both volume and proportion of the total plaque volume (if present). On histological evaluation of carotid endarterectomy specimens, each component was evaluated as an estimated proportion of total plaque volume. Results Of 80 included patients, 30 (37.5%) were female. The average age was 69.7 years (SD = 9.1). Based on imaging, intraplaque hemorrhage was the smallest contributor to plaque composition (1.2% of volumes on average). Statistically significant linear associations were noted between the proportion of intraplaque hemorrhage, lipid-rich necrotic core, and calcifications on histology and the volume of each component on imaging ( p values ranged from 0.0008 to 0.01). Area under curve were poor for intraplaque hemorrhage and lipid-rich necrotic core (0.59 and 0.61, respectively) and acceptable for calcifications (0.73). Conclusion Semi-automated analyses of computed tomography angiography have limited diagnostic accuracy in the detection of intraplaque hemorrhage and lipid-rich necrotic core in carotid artery plaques. However, volumetric imaging measurements of different components corresponded with histologic analysis.

Objective To systematically analyse prior reports of carotid endarterectomy (CEA) performed in cases of ≤50% carotid stenosis in order to understand patient tolerance and potential benefit. Methods A systematic review and descriptive analysis was performed in concordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. An English-language search was performed of online databases using librarian-selected search terms. Abstracts were reviewed for relevance which included mention of carotid endarterectomy and stenosis. Prospective or retrospective observational cohort studies that reported series of patients who underwent endarterectomy for minimal (≤50%) luminal stenosis with reported outcomes were included. Results Six studies (which included our institutional series) with a total of 143 patients met the inclusion criteria. The weighted mean age at the time of CEA was 72.3 years; 113 (79.0%) were male. 55.8% of patients with available data had recurrent ipsilateral ischaemic events despite medical therapy. Two patients out of 129 with available perioperative data (1.6%) had perioperative MRI findings of acute ischaemic stroke, both within the hemisphere contralateral to the side of CEA. Of the 138 patients with available follow-up (mean, 36 months), none had recurrent ipsilateral ischaemic events. Conclusions Endarterectomy for symptomatic carotid disease causing ≤50% stenosis may be a potentially beneficial strategy to prevent stroke recurrence. Studies with robust methodology are needed to draw more definitive conclusions in terms of the safety and efficacy of endarterectomy for minimal stenosis with vulnerable features relative to intensive medical therapy.

Background and Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors. Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured. Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P <0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P <0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels ( P =0.010, r =−0.30) and directly with circulating uric acid levels ( P <0.001, r =0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P <0.001). Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.

Background Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). Methods and Results This retrospective observational cohort study enrolled 637 patients who underwent non‐invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow‐up of 5.3 years. Patients with PMED had lower IS‐free survival compared with patients without PMED (log‐rank P =0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10–10.63 ( P =0.03); adjusted HR of 3.70, 95% CI, 1.18–11.59 ( P =0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11–10.72 ( P =0.03) after adjusting for CHA 2 DS 2 ‐VASc score; adjusted HR of 5.70, 95% CI, 1.40–23.29 ( P =0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA 2 DS 2 ‐VASc score and revised Framingham Stroke Risk Score. Conclusions PMED was associated with a >3‐fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.

Background: Serum uric acid is a marker of oxidative stress, and may serve as a marker of adverse cardiovascular events and outcomes including cardiovascular death, hospitalization and myocardial infarction. We aimed to determine whether uric acid predicts cardiovascular events and death in patients undergoing carotid endarterectomy (CEA). Methods: We enrolled 327 patients undergoing CEA between February 2002 and June 2017 who had complete laboratory work up at baseline. Patients were followed through the electronic chart as well as via regular nursing follow-up for a median of 10.9 years (IQR 7.3, 13.4). There were a total of 67 adverse cardiovascular events during follow-up. Results: Baseline serum uric acid levels were significantly higher in patients who developed cardiovascular events during the follow-up period vs. those that did not [6.87 + 2.29 vs. 6.39 + 1.61); p=0.047). Baseline serum uric was independently associated with cardiovascular events when adjusting for age, creatinine, diabetes mellitus, and hyperlipidemia (L-R 4.0, p=0.04)(Figure 1). Sex stratified analysis showed that serum uric acid was also an independent predictor of both cardiovascular events and death in men, not women undergoing after adjustment for confounders including age, cholesterol, systolic blood pressure and glucose (LR 4.97; p=0.03). Discussion: Higher uric acid levels are associated with cardiovascular events and death after CEA. Further investigation is necessary to determine the role of uric acid as a modifiable risk factor in these patients.

Background: Uric acid is a known risk factor for atherosclerosis. We aimed to determine whether baseline uric acid levels predict plaque stability on presentation and future cerebrovascular events (CVA) in patients undergoing carotid endarterectomy (CEA). Methods: We analyzed 317 patients who underwent CEA between 2/2002 and 6/2017. Patients were stratified according to plaque stability as unstable or stable --those who presented with a history of > 1 neurologic event were “unstable” and those with no history of CVA were classified as stable. All patients underwent comprehensive baseline laboratory testing at baseline prior to CEA and then were followed by a nurse coordinator and through the medical record for the development of cerebrovascular events including stroke and transient ischemic attack for a median of 10.9 years (IQR 7.3, 13.4). Results: Baseline uric acid was significantly higher in patients presenting with unstable plaque vs. stable plaque(6.5 (IQR 5.6, 7.9) vs. 5.8(IQR 4.8,6.6); p<0.001), and was an independent predictor of plaque stability when adjusting for potential confounders including glucose, BMI, hsCRP, cholesterol, and systolic blood pressure (L-R 6.9, p=0.0096). There were a total of 58 CVA during follow-up, and baseline uric acid was higher among patients who developed CVA vs those without CVA [(6.9 + 2.1) mg/dL vs. (6.4 + 1.7) mg/dL; p=0.037]. After adjusting for diabetes, cholesterol, systolic blood pressure, smoking , age, aspirin, and creatinine, uric acid and cholesterol were both independent predictors of stroke in this population [uric acid: (LR 4.84, p=0.03); cholesterol: (L-R 11.8, p=0.0006)]. Discussion: While cholesterol has been associated with poor outcomes in patients with vascular disease, our data suggest that uric acid may be a novel risk factor for stroke in patients undergoing CEA. Further investigation is necessary to understand the therapeutic potential of reducing uric acid levels in these patients and the potential benefit of reducing overall cerebrovascular risk.

Background: High sensitivity C-reactive protein is a risk factor atherosclerosis and plaque rupture. We aimed to determine the role of high-sensitivity C reactive protein in predicting future cerebrovascular events (CVA), including stroke and transient ischemic attack, in patients undergoing routine carotid endarterectomy (CEA). Methods: A total of 251 patients underwent routine CEA without any history of stroke. At baseline prior to CEA, patients underwent routine laboratory testing, including testing for novel biomarkers including hs-CRP. Patients were followed for a median of 10.9 years (IQR 7.3, 13.4) for the development of CVA with regular nursing follow-up and/or chart review. Results: Of 251 patients enrolled in the study, 19 patients without prior CVA subsequently developed CVA during follow-up. In univariate analysis, baseline hsCRP was significantly higher in patients who developed CVA during follow-up vs. those that did not (8.1 (IQR 2.2, 46.3) mg/L vs. 3.85(0.9, 11.75) mg/L; p=0.0054)(Figure 1). After adjusting for confounders including age. diabetes mellitus, cholesterol, systolic blood pressure, history of smoking, aspirin use and duration of follow-up, log hsCRP was an independent predictor of CVA during follow-up after CEA (L-R 9.9; p=0.0016). Discussion: Hs-CRP appears to be a risk factor for CVA during follow-up after CEA. Further investigation is necessary to determine the role of risk modification in these patients and the therapeutic potential of reducing inflammation in this population.