Severe Atherosclerotic Plaques Research Articles

Relationships between neighborhood disadvantage and cardiovascular findings at autopsy in subjects with sudden death

Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n=607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n=857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P=0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P=0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P=0.004). However, these associations were omitted after adjustment for traditional risk factors and race. Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.

Abstract 13995: Relationships Between Neighborhood Disadvantage and Cardiovascular Findings at Autopsy in Subjects With Sudden Death

Introduction: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. Methods: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip-codes. Area Deprivation Index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. Results: Subjects from most disadvantaged neighborhoods ( i.e. , ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods ( i.e. , ADI ≤ 7; n = 857; 46.07 ± 14.10 versus 47.78 ± 13.86 years; p = 0.02) and were more likely Black or women. They were, however, less likely to die from cardiac causes of death (61.8% versus 67.7%; p = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% versus 25.1%, p = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. Conclusion: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in cardiovascular pathology.

Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation.

The cysteine674 (C674) thiol of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 is easily and irreversibly oxidized under atherosclerotic conditions. However, the contribution of the C674 thiol redox status in the development of atherosclerosis remains unclear. Our goal was to elucidate the possible mechanism involved. Heterozygous SERCA2 C674S knock-in mice in which half of the C674 was substituted by serine (S674) were used to mimic the removal of the reactive C674 thiol, which occurs under pathological conditions. Bone marrow-derived macrophages (BMDMs) and cardiac endothelial cells (ECs) were used for intracellular Ca2+ , macrophage adhesion, and protein expression analysis. The whole aorta and aortic root were isolated for histological analysis. Cell culture studies suggest the partial substitution of SERCA2 C674 increased intracellular Ca2+ levels and induced ER stress in both BMDMs and ECs. The release of proinflammatory factors and macrophage adhesion increased in SKI BMDMs. In ECs, overexpression of S674 induced endothelial inflammation and promoted macrophage recruitment. SKI mice developed more severe atherosclerotic plaque and macrophage accumulation. Additionally, 4-phenyl butyric acid, an ER stress inhibitor, suppressed ER stress and inflammatory responses in BMDMs and ECs, and alleviated atherosclerosis in SKI mice. The substitution of SERCA2 C674 thiol accelerates the development of atherosclerosis by inducing ER stress and inflammation. Our findings highlight the importance of SERCA2 C674 redox state in the context of atherosclerosis and open up a novel therapeutic strategy to combat atherosclerosis.

The relationship between lack of educational attainment, cardiovascular risk factors, atherosclerosis and coronary artery disease

Educational attainment is related to improved health and longevity. We investigated the relationship between educational attainment and cardiovascular risk factors, subclinical atherosclerosis, and incidence of coronary artery disease. The Reykjavik REFINE study is a population-based study recruiting 6616 subjects, 25-69 years of age from the greater Reykjavik area in 2005-2011. Baseline measurements of cardiovascular risk factors were performed, and all participants had a carotid ultrasound examination to detect subclinical atherosclerotic lesions. Clinical follow-up of cardiovascular disease during a ten-year period was performed. Educational attainment was related to clinical outcome measures. The study population comprised of 3251 men and 3365 women. The proportion of the study population with primary school education only was 20.1%, 31.2% had vocational training, 12.3% had high school education and 36.4% were university graduates. Traditional cardiovascular risk factors were generally higher among subjects with primary school education only. Compared to subjects with university education, the odds ratio of having severe atherosclerotic plaque was 1.84 (95% CI 1.40-2.43) among those with primary school education only and 1.49 (95% CI 1.16-1.91) among subjects with vocational training. The subjects with high school or university education were less likely to develop significant cardiovascular disease during the 10-year follow-up period. Primary school and vocational training compared to university education are associated with risk factors of atherosclerotic disease, subclinical carotid plaque, and incidence of cardiovascular disease. The reason for this disparity remains to be clarified but socioeconomic inequality related to less educational attainment might be involved.

Abstract 241: Nicotinamide Nucleotide Transhydrogenase Regulates Mitochondrial Function And Oxldl Induced Macrophage Endothelial Interaction.

Atherosclerosis is a chronic inflammatory disease effecting large and medium sized arteries that leads to the buildup of plaque that contributes to myocardial infraction, stroke, and other pathologies. Mounting evidence has identified mitochondrial reactive oxygen species (ROS) as a key contributor to plaque formation and progression. A inner mitochondrial membrane enzyme Nicotinamide nucleotide transhydrogenase (NNT) sustains NADPH pools required for the mitochondrial antioxidant systems. We have observed that the expression of NNT is decreased in severe human atherosclerotic plaques leading us to hypothesize that the loss of NNT contributes to increased mitochondrial ROS and drives the progression of atherosclerosis by enhancing endothelial and vascular dysfunction. Utilizing AAV/PCSK9 and HFD induced models of early and late-stage atherosclerosis, we found that NNT knockout (NNT KO) mice display significantly increased VCAM-1 expression in aortic endothelial cells during early atherosclerosis and significantly larger necrotic cores in late-stage atherosclerosis. Additionally, NNT KO mice displayed a significantly thinner fibrous cap in late-stage plaques. Similar results were observed in vitro where the loss of NNT in human aortic endothelial cells exacerbated oxLDL induced VCAM-1 expression that was associated with decreased mitochondrial NADPH levels, glutathione peroxidase (Gpx2) activity, and increased H 2 O 2 production. The observed increase in necrotic core area in NNT KO mice is suggestive of increased inflammatory cell recruitment to the plaque. Furthermore, bone marrow derived macrophages (BMDM) from NNT KO mice display decreased lipid content, poor lipid uptake and a predisposition to differentiate into a proinflammatory M1 phenotype. Based on these studies, we conclude that the loss of NNT contributes to unstable plaques with large necrotic cores, mitochondrial ROS driven endothelial dysfunction, increased inflammatory cell recruitment, and enhanced M1 macrophage activity. The novel relationship between vascular NNT expression and plaque severity in human samples implicates NNT as a novel clinical target in atherosclerosis.

Abstract 15301: Peripheral CD56 bright Natural Killer Cells Associate With Increased Atheroburden and Unstable Plaque Features in Humans

Background: Atherosclerotic plaques in mice and humans contain natural killer (NK) cells. Data on the role of NK cells in atherosclerosis using different transgenic mice models is inconsistent. Some studies showed that NK cells augment atherosclerosis through their cytotoxic potential, while others reported no effect. Evidence in humans indicates that NK cells are atherogenic. Frequency of NK cells and expression of the activating NK cell receptors are associated with severe disease and symptomatic carotid atherosclerotic plaques in humans. Hypothesis: We tested if coronary artery disease (CAD) subjects with necrotic plaques have a higher frequency of the circulating NK cells. Methods: We performed mass cytometry on peripheral blood mononuclear cells from matched CAD subjects with low and high (n=9 each) necrotic plaque content as determined by intravascular ultrasound-virtual histology. Results: CAD subjects with high necrotic plaques have significantly higher atheroburden, stenosis, calcium, fatty plaque content, and lower plaque fibrosis. Interestingly, CAD subjects with high necrotic plaques exhibited a significantly higher frequency of the CD56 bright NK cells as compared to those with low necrotic plaques (4.618 ± 0.625 vs 2.481 ± 0.37; p=0.011). Moreover, frequency of CD25 + NK cells also trended to be higher in subjects with high necrotic plaques. The frequency of the cytotoxic CD56 dim NK cells did not differ between the two groups. Correlation analyses demonstrated a significant positive association of CD56 bright NK cells with atheroburden (r=0.43; p=0.04), stenosis (r=0.58; p=0.005), plaque necrotic (r=0.71; p=0.002), calcium contents (r=0.73; p=0.0001), and a negative association with the plaque fibrous content (r=0.71; p= 0.0003). CD25 + NK cells also showed similar trending associations with burden, stenosis and plaque features. Conclusions: Our data provides yet another evidence of the atherogenic role of NK cells in humans and indicates that the CD56 bright NK cells may contribute to the development of a vulnerable plaque. CD56 bright NK cells produce proinflammatory cytokines including IFN-γ and TNF-α and cytotoxic enzymes that may contribute to increased inflammation, cell activation, and apoptosis within the plaque.

Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction.

Ischemic heart disease still represents a large burden on individuals and health care resources worldwide. By conventions, it is equated with atherosclerotic plaque due to flow-limiting obstruction in large–medium sized coronary arteries. However, clinical, angiographic and autoptic findings suggest a multifaceted pathophysiology for ischemic heart disease and just some cases are caused by severe or complicated atherosclerotic plaques. Currently there is no well-defined assessment of ischemic heart disease pathophysiology that satisfies all the observations and sometimes the underlying mechanism to everyday ischemic heart disease ward cases is misleading. In order to better examine this complicated disease and to provide future perspectives, it is important to know and analyze the pathophysiological mechanisms that underline it, because ischemic heart disease is not always determined by atherosclerotic plaque complication. Therefore, in order to have a more complete comprehension of ischemic heart disease we propose an overview of the available pathophysiological paradigms, from plaque activation to microvascular dysfunction.

Genetic deficiency of Phactr1 promotes atherosclerosis development via facilitating M1 macrophage polarization and foam cell formation.

Genetic variants in phosphatase and actin regulator-1 (Phactr1) are reported to be associated with arteriosclerotic cardiovascular disease (ASCVD). However, the function of Phactr1 in atherosclerosis remains unclear. Patients with acute coronary syndrome (ACS) who underwent coronary angiography and optical coherence tomography (OCT) were enrolled and divided into non-ST segment elevation (NST-ACS) group and ST-ACS group. The expression of Phactr1 on monocytes was higher in NST-ACS and ST-ACS groups as compared with control group. Furthermore, NST-ACS patients who have more vulnerable features including thin-cap fibroatheroma (TCFA) and large lipid area showed higher levels of Phactr1 on monocytes than those with stable plaques. Through mouse models of atherosclerosis, Phactr1-/-Apoe-/- mice (double knockout mice, DKO) developed more severe atherosclerotic plaques, recruiting more macrophages into subendothelium and having elevated levels of proinflammatory cytokines in plaques. Similarly, Apoe knockout mice (Apoe-/-) receiving DKO bone marrow (BM) exhibited elevated plaque burden compared with Apoe-/- mice receiving Apoe-/- BM, indicating the protective effect of Phactr1 in hematopoietic cells. We found that depletion of Phactr1 in BM-derived macrophages (BMDMs) tended to differentiate into M1 phenotype, produced more proatherogenic cytokines and eventually converted into foam cells driven by oxidized low-density lipoprotein (ox-LDL). Mechanistically, Phactr1 activated CREB signaling via directly binding to CREB, up-regulating CREB phosphorylation and inducing KLF4 expression. Finally, overexpression of KLF4 partly rescued the excessive inflammation response and foam cell formation induced by deficiency of Phactr1. In conclusion, our study demonstrates that elevated Phactr1 in monocytes is a promising biomarker for vulnerable plaques, while increased Phactr1 attenuates atherosclerotic development via activation of CREB and M2 macrophage differentiation.

Single-Stage Hybrid Arch Repair for Patients with Shaggy Aorta.

Operating on extended arch aneurysms that contain severe atherosclerotic plaques is difficult. In such cases, the incidence of intraoperative multiple embolization is very high. We applied single-stage hybrid arch repair, which involved ascending aorta replacement and debranching of arch vessels, consecutively with endovascular repair for two patients. This technique was developed to prevent embolization of atherosclerotic plaques during cardiopulmonary bypass, and abrasion of the plaques during thoracic endovascular repair. Both patients recovered without embolic complications.

456Risk of arterial calcification by conventional vitamin K antagonist treatment

Abstract Background Vitamin K antagonists (VKA) are the most frequently prescribed oral anticoagulants worldwide although new oral anticoagulants (NOAC) have become an important alternative. VKA inhibits Vitamin K1 necessary to produce coagulation factors but also Vitamin K2, which is essential in the activation of matrix-Gla protein, thought to be a strong local inhibitor of arterial calcifications. Purpose The aim was to investigate, whether VKA treatment is associated with coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD). Methods We collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n=9,672) or research studies (n=14,166) in the period 2007–2017. Data on use of VKA and NOAC was obtained from the Danish National Health Service Prescription Database. The association between VKA treatment duration and categorized CAC score was investigated by ordered logistic regression while adjusting for covariates. The independent variables included in the model were: age, gender, smoking, body mass index (BMI), diabetes mellitus, hypertension, hypercholesterolemia and/or statin treatment, family history of CVD, estimated glomerular filtration rate, VKA treatment duration and NOAC treatment duration. The categorisation of CAC was: 0, 1–99, 100–399 and ≥400 AU, corresponding to no, mild, moderate and severe atherosclerotic plaque burden, respectively. Results The final study population consisted of 17,254 participants (median 67 years old, 75% males) with no prior CVD, of which 1,748 (10%) and 1,144 (7%) had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories (Figure). For each cumulative year of VKA treatment, the odds of being in a higher CAC category, i.e. having more severe atherosclerosis, increased (odds ratio (OR)=1.032, 95% CI 1.009–1.057). All traditional cardiovascular risk factors were also associated with CAC. In contrast, NOAC treatment duration was not associated with CAC category (OR=1.004, 95% CI 0.937–1.075). In a sensitivity analysis of patients without statin treatment (n=12,143), the association between VKA treatment and CAC category remained unchanged. There was no significant interaction between VKA treatment duration and age on CAC category. Conclusion Adjusted for cardiovascular risk factors, VKA treatment – in contrast to NOAC - is associated with more severe CAC. Additional studies are required to clarify the clinical importance of this association in terms of hard cardiovascular endpoints. Acknowledgement/Funding Novo Nordisk Foundation and Independent Research Fund Denmark

A Rare Case of Severe Ischemic Gastropathy Causing Upper GI Bleed

Ischemic gastropathy is an uncommon diagnosis due to the extensive arterial collaterals that supply the stomach. Hence, its diagnosis is infrequently entertained in patients presenting with upper GI bleed. A 76 year-old woman with hypertension, hyperlipidemia, and chronic kidney disease presented with acute onset shortness of breath. She was tachycardic, tachypneic, and hypotensive. On exam she had rales, expiratory wheezes, and abdominal distention. Labs showed elevated lactate of 3.27 mmol/L, metabolic acidosis, leukocytosis of 22 K/uL, and normal hemoglobin. She was managed for acute hypoxemic respiratory failure and sepsis secondary to pneumonia. Despite treatment of her sepsis, lactic acidosis persisted > 2mmol/L. An abdominal CT was obtained to evaluate distention showed pneumatosis intestinalis. IV metronidazole was started to treat gas forming organisms, with an immediate improvement in WBC from 24 to 8.6 K/uL. There were episodes of melena requiring a total of 9 units of PRBCs. EGD was done and showed extensive shallow ischemic ulcers involving most of the anterior gastric wall and denuded duodenal mucosa. Subsequent CT angiography of the abdomen showed severe atherosclerotic plaques causing focal high grade stenosis at the celiac axis and lesser stenosis of the superior mesenteric artery, and complete resolution of pneumatosis intestinalis. An IR guided stent was placed across the celiac with successful reperfusion confirmed by fluoroscopy. Serum lactate levels rapidly normalized and a repeat EGD three weeks later showed near complete resolution of the gastric ulcers.2679_A Figure 1. Pneumatosis intestinalis.2679_B Figure 2. Large ischemic gastric ulcers.2679_C Figure 3. Healing ischemic gastric ulcers s/p stent placement.Gastric ischemia may be secondary to systemic hypoperfusion in the setting of shock or local splanchnic vessel stenosis or thrombosis. Ischemia leads to gastric mucosal barrier dysfunction, accumulation of gastric acid, and subsequent ulceration. Our patient had episodes of global hypoperfusion as well as local atherosclerosis. She was also on intermittent hemodialysis, which has been shown to cause accelerated rates of atherosclerosis. Ischemic gastropathy is a rare cause of upper GI bleeding. Hence, it is important to consider in patients with persistent lactic acidosis and non-healing gastric ulcers despite proton pump inhibitors. While ischemia secondary to transient low flow states may be managed conservatively with bowel rest and broad spectrum antibiotics, definitive recanalization of the celiac trunk may be required when high grade stenosis is present.

Image-based assessment of uncertainty in quantification of carotid lumen.

Measurements of the vessel lumen diameter are often used to determine the degree of atherosclerotic disease in carotid arteries. However, quantification results vary with imaging technique and acquisition settings. We aim at providing a tool that quantifies the lumen diameter on different image datasets and gives an estimate of quantification uncertainties, so that they can be taken into consideration when evaluating and comparing measurements. For the segmentation of the vessel lumen, we present an algorithm using ray-casting techniques and partial volume correction. We furthermore propose a scheme for the analysis and exploration of the lumen diameter. Finally, we present a clinically relevant application scenario, in which we explore agreement between lumen diameter estimations in corresponding computed tomography angiography, contrast-enhanced magnetic resonance angiography, time-of-flight, and subtraction images of carotid vessels with severe carotid atherosclerotic plaques.

Is transesophageal echocardiography needed for evaluating tissue-based transient ischemic attack?

Transient ischemic attack (TIA) is a warning signal for stroke. A comprehensive evaluation of TIA may reduce the risk for subsequent stroke. Data on the findings of cardiac evaluation with transesophageal echocardiography (TEE) in patients with TIA are sparse. Our aims were to determine the frequency of TEE performance and to investigate the findings of TEE in patients with TIA based on the new definition of TIA (i.e., transient neurological symptoms without evidence of infarction). During a 4-year period (2011–2014), 1071 patients (mean age, 70 ± 13 years; female, 49.7%) with TIA were included in a prospective study and evaluated. Of 1071 consecutive patients suffering from TIA, 288 patients (27%) underwent TEE. The median time between admission and TEE was 6 days. Patients with TIA who were evaluated by TEE were younger (67 vs. 71 years, P < 0.001) than those who were not evaluated by TEE. They had a higher rate of sensibility disturbance as a TIA symptom (39% vs. 31%, P = 0.012) but a lower rate of previous stroke (15% vs. 25%, P = 0.001) and atrial fibrillation (2% vs. 21%, P < 0.001) than those who did not. Foramen ovale was detected in 71 patients (25.7%), atrial septal aneurysm in 13 patients (4.6%), and severe atherosclerotic plaques (grade 4 and 5) in the aortic arch in 25 patients (8.7%). One patient (0.3%) had a fibroma detected by TEE. In 17 of the 288 patients (6%) who underwent TEE, the indication for anticoagulation therapy was based on the TEE results, and 1 patient with fibroma underwent heart surgery. During hospitalization, 7 patients experienced a subsequent stroke, and 27 patients had a recurrent TIA. At 3 months following discharge, the rates of readmission, stroke, recurrent TIA, and death were 19%, 2.7%, 4.2%, and 1.6%, respectively. The rates of mortality (0.9% vs. 1.8%, P = 0.7), stroke risk (1.9% vs. 3.0%, P = 0.8), and recurrent TIA (5.0% vs. 3.9%, P = 0.8) were similar in patients who underwent TEE and in those who did not. Performing TEE in patients with tissue-based TIA is helpful in detecting cardiac sources for embolism and may indicate for anticoagulation.

MicroRNA-182 Promotes Lipoprotein Lipase Expression and Atherogenesisby Targeting Histone Deacetylase 9 in Apolipoprotein E-Knockout Mice.

Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.

High titer of anti-citrullinated peptide antibody is a risk factor for severe carotid atherosclerotic plaque in patients with rheumatoid arthritis: the TOMORROW study.

Cardiovascular disease is one of the complications of rheumatoid arthritis (RA). We researched the morbidity and severity of existing carotid atherosclerosis plaque and associated risk factors in patients with RA. This study included 413 participants, including 208 patients with RA and 205 age- and sex-matched healthy volunteers. Carotid ultrasound, clinical data collection and assessment of cardiovascular risk factors were performed. Atherosclerotic plaque was defined as an intima-media thickness ≥ 1.1 mm. Severity of plaque was assessed by plaque score, defined as the sum of the maximal thickness of all plaques in bilateral carotid arteries. Data were analyzed from 200 patients with RA and 202 controls. Carotid plaque was observed more frequently in patients with RA than controls (47.0 vs. 36.1%, P = 0.027). Moreover, plaque score was significantly higher in RA patients (P = 0.032). In logistic regression analysis, RA represented an independent risk factor for the presence of plaque (adjusted odds ratio, 1.68; 95% confidence interval, 1.03-2.74). Comparing RA patients with and without plaque, anti-cyclic citrullinated peptide (anti-CCP) antibodies titer was significantly higher in patients with plaque (315.8 ± 454.1 U/mL) than in patients without (165.7 ± 281.1 U/mL; P = 0.005). Moreover, multiple linear regression analysis clarified that anti-CCP antibody titer was associated with plaque score in patients with RA. High prevalence of any carotid plaques and severe carotid plaques were more frequent in patients with RA. High titer of anti-CCP antibodies represented a risk factor for severe carotid atherosclerotic plaque in patients with RA.

Numerical simulation of haemodynamics and low-density lipoprotein transport in the rabbit aorta and their correlation with atherosclerotic plaque thickness.

Two mechanisms of shear stress and mass transport have been recognized to play an important role in the development of localized atherosclerosis. However, their relationship and roles in atherogenesis are still obscure. It is necessary to investigate quantitatively the correlation among low-density lipoproteins (LDL) transport, haemodynamic parameters and plaque thickness. We simulated blood flow and LDL transport in rabbit aorta using computational fluid dynamics and evaluated plaque thickness in the aorta of a high-fat-diet rabbit. The numerical results show that regions with high luminal LDL concentration tend to have severely negative haemodynamic environments (HEs). However, for regions with moderately and slightly high luminal LDL concentration, the relationship between LDL concentration and the above haemodynamic indicators is not clear cut. Point-by-point correlation with experimental results indicates that severe atherosclerotic plaque corresponds to high LDL concentration and seriously negative HEs, less severe atherosclerotic plaque is related to either moderately high LDL concentration or moderately negative HEs, and there is almost no atherosclerotic plaque in regions with both low LDL concentration and positive HEs. In conclusion, LDL distribution is closely linked to blood flow transport, and the synergetic effects of luminal surface LDL concentration and wall shear stress-based haemodynamic indicators may determine plaque thickness.

SERCA inhibition attenuates medial thickening in an organ culture model of coronary artery disease

Atherosclerotic coronary artery disease (CAD) involves de‐differentiation of coronary smooth muscle (CSM) from a quiescent, contractile phenotype to a proliferative, migratory phenotype. We tested the hypothesis that sarco‐endoplasmic reticulum Ca2+ ATPase (SERCA) function is causal in CSM transition from contractile to proliferative. We measured proliferation with immunohistochemical analysis of Ki‐67 expression in both mild and severe atherosclerotic plaques. Ki‐67 expression peaks early in CAD progression, dropping off in severe CAD, likely because CSM either further differentiate into osteogenic CSM or become apoptotic. We concurrently examined SERCA function with fura‐2 assessment of caffeine‐induced sarcoplasmic reticulum (SR) Ca2+ store release and subsequent recovery. SERCA function is elevated in mild, early CAD and decreases in more advanced, severe CAD, mirroring Ki‐67 expression patterns. We cultured coronary arterial segments in DMEM with 180 mg/dL glucose and 20% fetal bovine serum for fourteen days, in the presence and absence of the selective SERCA inhibitor, cyclopiazonic acid (CPA). Initial results indicated that CPA treatment completely prevented culture‐induced medial thickening as assessed by histological staining. CSM were enzymatically dispersed and loaded with fura‐2/AM. CPA was absent from the dispersal and experimental solutions. SR Ca2+ store release and subsequent recovery below baseline levels were increased in CSM from CPA‐treated arteries, suggesting that functional inhibition induces of SERCA expression. We will examine SERCA and Ki‐67 expression in future studies to further examine the role of SERCA in the contractile‐to‐proliferative transition in atherosclerotic CAD.Support or Funding InformationNIH HL062552, IUSM CECARE, AHA 15PRE25280001

OUTBACK catheter for treatment of superficial femoral and iliac artery chronic total occlusion: Experience from two centers.

Purpose:The OUTBACK® catheter is a reentry device that enables reentry into a vessel lumen from the subintimal space during subintimal angioplasty. It is reserved for cases where reentry has not been possible using conventional wire and catheter techniques. We report a two-center experience in recanalization of the chronic total occlusions of the common iliac (CIA) and the superficial femoral artery (SFA) using the OUTBACK® catheter in cases where other techniques were unsuccessful.Material and Methods:All cases where recanalization was performed using the OUTBACK® reentry catheter between January 2010 to January 2015 were retrospectively identified and included in this study. 21 patients were identified. The indication for intervention in these cases included claudication and critical leg ischemia. In all cases, conventional recanalization could not be successfully achieved.Results:The OUTBACK® catheter was used to recanalize 10 SFA occlusion and 9 CIA occlusions. In 19 patients (90%), reentry into true arterial lumen was successfully achieved. 17 patients had their recanalization through the transfemoral approach whereas 2 patients had a transpopliteal artery approach. In 2 patients, reentry into the true lumen could not be achieved using the OUTBACK® catheter due to patient's intolerability for the procedure and severe atherosclerotic calcified plaques. There was 100% patency of the vessel intervened on Duplex ultrasound at 24 months of follow up. 16 patients (84%) remained asymptomatic and 2 patients (10.5%) reported worsening of their symptoms due to the development of new lesions within the arterial system.Conclusion:The OUTBACK® catheter is an effective and safe technique for reentry into the vessel lumen when conventional techniques fail.

Biphasic alterations in coronary smooth muscle Ca2+ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome

Background and aimsCoronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca2+ regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca2+ regulation at several time points during CAD progression. MethodsMetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca2+ was assessed with fura-2. ResultsIVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca2+ in CSM cells revealed heightened Ca2+ signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months = 1.8 ± 0.6 g, 9 months = 5.0 ± 1.0 g, 12 months = 0.7 ± 0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca2+ regulation and decreased proliferation compared to CSM from the wall. ConclusionsThese CSM Ca2+ regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up-vs. down-regulation of CSM Ca2+ regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca2+ contribute to progression of atherosclerotic CAD in MetS.

Transapical aortic valve replacement complicated by periaortic hematoma.

Abstract A 77-year-old woman with severe symptomatic aortic stenosis (aortic valve areaZ0.6 cm2 and mean gradientZ 53 mmHg) was deemed inoperable for surgical aortic valve replacement due to a porcelain aorta, and was scheduled for transcatheter aortic valve replacement via an apical approach. A 23 mm valve was selected based on a computerized axial tomographic angiography derived area of 360 mm2; valve oversizing was 15.4%. Baseline transesophageal echocardiography revealed severe protruding atheroma within the lumen of the ascending aorta. Immediately following deployment of the Sapien pericardial tissue valve (Edwards Life Sciences, Irvine, CA, USA), a large posterior periaortic hematoma was noted (1.3 cm in maximum width, and w4 cm in length) (see Fig. 1 and Videos 1, 2, 3, 4). Protamine was administered, and the hematoma was observed by transesophegeal echocardiography for w30 min with no change in size; function of the bioprosthetic valve was normal without regurgitation. In the immediate post-operative period, anti-platelet agents were withheld, and blood pressure was aggressively lowered. The remainder of her hospital course was uncomplicated, and a tranthoracic echocardiogram w1 month later demonstrated resolution of the hematoma. Periaortic hematoma and aortic root rupture are recognized potential major complications of transcatheter aortic valve replacement (1, 2). Severe left ventricular outflow tract calcification and annular over sizing are both risk factors for these complications. Careful transesophageal echocardiographic examination post valve deployment may lead to early recognition and treatment of this potentially fatal complication (3). In this case, presence of severe protruding atherosclerotic plaque pre-procedure likely predisposed to this complication.