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Thoracic aortic aneurysm and dissection are complex diagnoses that require management by multidisciplinary providers using a variety of medical therapies, surgical interventions, and lifestyle modifications. Pharmacological agents, such as β-blockers (atenolol) and angiotensin II type 1 receptor blockers (losartan), have been mainstay treatments for several years, and research from the past decade has continued to evaluate these and other medication classes to further improve patient morbidity and mortality. Combination β- and renin-aldosterone-angiotensin blockade, statins, metformin, antioxidants, and vitamins have been evaluated as therapeutics in both thoracic and abdominal aortic aneurysms, as well as the effects of various antibiotics (ie, fluoroquinolones and tetracyclines) and benefits of lifestyle modifications (eg, diet and exercise) and enhanced patient-centered care and treatment adherence. In addition, as our understanding of the genetic, biochemical, and pathophysiological mechanisms behind these diseases expands, so do potential targets for future therapeutic research (eg, interleukins, matrix metalloproteases, and mast cells). This review incorporates the major meta-analyses, systematic and generalized reviews, and clinical trials published from 2010 through 2021 that focus on these topics in thoracic aortic aneurysms (and abdominal aneurysms when thoracic literature is scarce). Several key ongoing clinical trials, case studies, and in vivo/in vitro studies are also mentioned. Furthermore, we discuss current gaps in the literature and the abundance of clinical evidence for some interventions in abdominal aneurysms with few thoracic correlates, thus indicating a need for investigation of these subjects in the latter.

Pregnancy-associated aortic dissection (AD) is a rare event, with an incidence of 0.0004% per pregnancy. The work of the Aortic Dissection Collaborative identified pregnancy-associated AD as a high-priority topic, despite its rarity. The Pregnancy Working Group, which included physicians and patient stakeholders, performed a systematic literature review of pregnancy-associated AD from 1960 to 2021 and identified 6,333 articles through PubMed, OVID MEDLINE, Cochrane, Embase, CINAHL and Web of Science. The inclusion criterion was AD in pregnant populations and exclusion criteria were case reports, conference abstracts, and languages other than English. Assessment of full-text articles for eligibility after removal of duplicates from all databases yielded 68 articles to be included in the final review. Topics included were timing of AD in pregnancy, type of AD, and management considerations of pregnancy-associated AD. The Pregnancy Working Group identified gaps in knowledge and future areas of research for pregnancy-associated AD, including clinical management, mental health outcomes post AD, reproductive and genetic counseling, and contraception after AD. Future collaborative projects could be a multicenter, international registry for all pregnancy-associated AD to refine the risk factors, best practice and management of AD in pregnancy. In addition, future mixed methodology studies may be useful to explore social, mental, and emotional factors related to pregnancy-associated AD and to determine support groups' effect on anxiety and depression related to these events in the pregnancy and postpartum period.

Telemedicine uses telephone-based or any form of digital communication for remote clinical services. It has been a field of interest for the last century, with broader implementation of telemedicine technologies during the last 25 years. The COVID-19 pandemic was an impetus for the adoption of these technologies globally across all health care services, including patient care, surgical practice, and workflow. As part of the patient engagement work in the Aortic Dissection Collaborative, this topic was identified as an important patient-centered research topic. Telemedicine has been adopted increasingly in vascular surgery; however, there is little evidence on appropriate use of these technologies pertaining to treating patients with aortic dissection or aortopathy in general. This landscape review summarizes the uses of telemedicine applications pre and post pandemic in medicine and vascular surgery, with a particular focus on uses in aortopathy. Using common resource databases, we identified articles related to the history of telemedicine, its current utilization, and application to vascular surgery and/or aortopathy. We briefly review the history of telemedicine and illustrate a range of applications in medicine before the pandemic, along with its rapid uptake globally during the COVID-19 pandemic. The enablers and barriers to using telemedicine are explored, although as a whole there is satisfaction with its integration among patients and providers. To address these, we offer recommendations to address future research as it pertains to telemedicine technologies in aortic dissection.

Although the topics of surgical techniques and medical therapies have been widely studied in aortic dissection (AD), studies examining the short- and long-term impact of this event on mental health are largely lacking. Many of the studies have used the 36-Item Short Form Survey at variable time points after the event. However, AD as medical trauma has a complex impact on a person's identity. Its implications for emotional, mental, social, existential, and self-concept could be explored more robustly. This topic was identified as a topic of interest by the AD Collaborative. The AD Collaborative Mental Health Working Group was formed and performed a landscape review to summarize current literature surrounding quality of life research in those who have experienced AD, identify gaps in knowledge, and to outline future research questions.

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems. The Aortic Dissection Collaborative was established to define aortic dissection research priorities through patient engagement. Using a collaborative patient-centered feedback model, our Genomic Medicine Working Group identified related research priorities that could be investigated by pragmatic interventional studies aimed at aortic dissection prevention, utilization of genomic information to improve patient outcomes, and access to genomic medicine services. Further research is also needed to identify the genomic, lifestyle, and environmental risk factors that contribute to aortic dissection so these data can be incorporated into future comparative effectiveness studies to prevent aortic dissection.

Understanding what matters most to patients can help guide research in a direction that is best situated to provide evidence that is responsive to their core concerns. This can better inform the treatment decision-making process for patients and their physicians. The Aortic Dissection (AD) Collaborative built a collaborative AD research infrastructure involving patients and other stakeholders to facilitate patient-centered outcomes research training, support, and networking among those affected by AD. Two surveys and semi-structured interviews were conducted between January and October 2020 to gather information from people with and at risk for AD and their family members to better understand their experiences and needs. Discussion of survey and interview results were then articulated as seven key topics for future research to meet the needs of the AD community. Working groups were assembled to address each of the key topics. The groups conducted landscape reviews that were focused on providing guidance for future research that directly addresses the needs identified by the AD community. Recommendations for future research generated by the working groups were compiled by the Aortic Dissection Collaborative. From these recommendations, the Aortic Dissection Collaborative advisors and stakeholders identified high-priority research questions. The research questions form the basis for a third survey, disseminated to the Virtual Research Network between November 2021 and February 2022. Final analysis of the survey will identify top ranked research questions and assess willingness to participate. These results will inform the development of future patient-centered outcomes research and comparative effectiveness research proposals.

Aortic dissection (AD) is recognized as a potentially fatal condition and its standard treatment has been surgical intervention for acute type A AD (TAAD) and complicated acute type B AD (TBAD), and medical management for uncomplicated acute type B AD. Due to rapidly evolving device technologies and minimally invasive surgical techniques that have lowered perioperative risk, there are paradigm shifts for the indications and treatment options for both TAAD and TBAD. In this article, we will discuss the current indications and treatment options for TAAD and TBAD by chronicity of the disease, which comprises four categories: acute TAAD, chronic (repaired) TAAD, acute TBAD, and chronic TBAD. We will also discuss the knowledge gaps in the current surgical management strategies and literature evidence. Open surgical intervention remains the reference standard for acute TAAD and chronic TAAD with complications until an endoprosthesis that will suit the complex anatomy of aortic root, ascending aorta, and aortic arch is developed. Thoracic endovascular aortic repair is now the first line for complicated acute and chronic TBADs. However, we need a larger trials to support the safety and durability of the procedures in patients with uncomplicated TBAD. Without additional data, patients are left to choose between existing treatment options, such as open surgical repair and stent-grafting.

The Aortic Dissection (AD) Collaborative was established to evaluate patient-centered research priorities in AD. Education was identified as a topic of interest by the stakeholders. The AD Collaborative Education Working Group evaluated existing educational resources and identified areas amenable to comparative effectiveness research. The most important positive qualities of available AD education resources are ease of use, diversity of representation, accessibility, and organization. The most important negative qualities of these resources are non-patient-centered language, promotional themes, and those with limited applicability and accessibility. Through a series of focus groups, the Working Group identified target audiences for AD education and educational material content and critically assessed and prioritized barriers to effective AD education. Both the target audiences and the barriers include clinicians and patients themselves. The Working Group defined initiatives to overcome barriers, to include a comprehensive, universally agreed on AD resource that is updated in real time and making education accessible to all relevant target audiences. The Working Group then prioritized needs for comparative effectiveness research in AD education and determined that clinician education is the top priority for future efforts. The Working Group determined that assessment and evaluation of specific and appropriate screening strategies is the second most important priority. Finally, the Working Group identified patient education as the third most important priority, specifically determining how patients and their support groups learn best, the ideal strategies for information dissemination, and methods of assessing understanding and satisfaction with the education process.

Aortic dissection (AD) is a life-threatening rare disease that occurs as a spontaneous tear in the wall of the aorta. Survivors of AD go on to have a chronic disease process that requires lifelong follow-up and management. Although the COVID-19 pandemic has strained health systems and impacted practice in the United States, the effects of these impacts on people living with or at risk for AD is not well understood. This mixed methods project examined the experiences of people in the AD community during the COVID-19 pandemic between March and October 2020. Results reveal that the AD community lacked clear guidance on the role aortic health status plays in COVID-19 risk and experienced significant disruptions in aortic healthcare. At the same time, the new expansion in access to medical care with telehealth conferred unforeseen benefits in the form of reduced barriers for access to specialized aortic health care.

Aortic dissection (AD) is a life-changing event that is often accompanied by a loss of normal quality of life. Survivors of AD go on to have a chronic disease that requires lifestyle modification, medical management, and surgical repair of the aorta. Clinical care includes multiple disciplines, health care settings, and often different geographic locations. This qualitative assessment examined the experiences of people with and at risk for AD. The following four themes emerged: "unnecessary drama" at diagnosis, unmet needs for information and support, the burden of self-advocacy and care coordination, and living with unaddressed mental health impacts. Our findings inform recommendations to advance patient-centered care delivery for individuals with and at risk for AD, improving communication of timely and relevant information, and an approach to care that acknowledges the whole person in clinical decision making.

BACKGROUND: With a unique influenza season occurring in the midst of a pandemic, there is interest in assessing the role of the influenza vaccine in COVID-19 susceptibility and severity. METHODS: In this retrospective cohort study, patients receiving a laboratory test for COVID-19 were identified. The primary outcome was comparison of positive COVID-19 testing in those who received the influenza vaccine versus those who did not. Secondary end points in patients testing positive for COVID-19 included mortality, need for hospitalization, length of stay, need for intensive care, and mechanical ventilation. RESULTS: A total of 27,201 patients received laboratory testing for COVID-19. The odds of testing positive for COVID-19 was reduced in patients who received an influenza vaccine compared to those who did not (odds ratio 0.76, 95% CI 0.68-0.86; P

Background: Bicuspid aortic valve (BAV) is associated with an increased risk of aortic dissection, but little is known about pregnancy-associated outcomes. Methods: ICD codes and a text recognition program (EMERSE) were used to identify women with BAV and pregnancy (2000-2018) at a single center. Charts were manually reviewed to confirm the diagnoses, echocardiographic data, co-morbidities, and outcomes. Inclusion criteria were congenital BAV pathology and pregnancy. Primary endpoints included expansion of aortic aneurysm and aortic dissection during pregnancy and up to 6 weeks post-partum. Results: We identified 622 women with diagnoses of BAV and pregnancy. After detailed review, 72 women (87 pregnancies) met inclusion criteria. Mean gestational age at delivery was 36.9 weeks. Ten (11.5%) patients had hypertensive disorders of pregnancy, 7 (8.0%) had gestational diabetes, and 25 (28.7%) were treated with beta-blockers. Two (2.3%) pregnancies had intra-uterine growth restriction. Vaginal deliveries occurred in 56.5% and cesarean section in 36.3%. No Type A or B aortic dissections occurred. During pregnancy, there were no significant changes in the aortic dimensions. Prior to pregnancy, 6 women had aortic measurements > 40mm (mean pre-pregnancy 40.8 ± 3.2 mm; mean post-pregnancy 42.5 ± 3.9 mm). In this higher-risk group, mean gestational age was 38.7 weeks, 4 (66.7%) had vaginal delivery, 1 (16.7%) had preeclampsia, 4 (66.7%) were treated with beta-blockers, and all breastfed. There were no delivery complications, no aortic dissections, and no maternal or fetal deaths. Conclusions: Women with BAV appear to be at relatively low risk for acute aortic dissection during pregnancy.

Enzyme modified non-oxidative LDL (ELDL) is effectively taken up by vascular smooth muscle cells (SMC) and mediates transition into foam cells and produces phenotypic changes in SMC function. Our data show that incubation of human coronary artery SMC (HCASMC) with low concentration of ELDL (10 μg/ml) results in significantly enhanced foam cell formation compared to oxidized LDL (200 μg/ml; p

Triggering events for acute aortic dissections are incompletely understood. We sought to investigate whether there is an association between admission for acute type A aortic dissection (ATAAD) to the University of Michigan Medical Center and the reported annual influenza activity by the Michigan Department of Health and Human Services. From 1996–2019 we had 758 patients admitted for ATAAD with 3.1 admissions per month during November-March and 2.5 admissions per month during April-October (p = 0.01). Influenza reporting data by the Michigan Department of Health and Human Services became available in 2009. ATAAD admissions for the period 2009–2019 (n = 455) were 4.8 cases/month during peak influenza months compared to 3.5 cases/month during non-peak influenza months (p = 0.001). ATAAD patients admitted during influenza season had increased in-hospital mortality (11.0% vs. 5.8%, p = 0.024) and increased 30-day mortality (9.7 vs. 5.4%, p = 0.048). The results point to higher admission rates for ATAAD during months with above average influenza rates. Future studies need to investigate whether influenza virus infection affects susceptibility for aortic dissection, and whether this risk can be attenuated with the annual influenza vaccine in this patient population.

Importance Thoracic aortic aneurysms leading to acute aortic dissections are a major cause of morbidity and mortality despite significant advances in surgical treatment, which remains the main intervention to prevent type A dissections. In the past 2 decades progress has been made toward a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta. This focused review emphasizes the results of clinical trials using β-blocker, losartan potassium, and irbesartan in patients with Marfan syndrome and comments briefly on mechanisms of aortic remodeling, including fibrosis and transforming growth factor β signaling. Observation The major risk factors for the disease are increased hemodynamic forces, typically owing to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease have been shown or are predicted to decrease vascular smooth muscle cell contraction, decrease transforming growth factor β signaling, or alter the extracellular matrix. Preclinical models of Marfan syndrome showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than β-blockers. Most importantly, clinical trials assessing whether losartan therapy not only reduces aortic growth but also improves adverse aortic outcomes, including dissection, need for surgery, and death, have not been conducted. The largest trial to date to our knowledge, the Pediatric Heart Network trial, sponsored by the National Heart, Lung, and Blood Institute, showed a nonsignificant increase in adverse aortic outcomes, with almost a doubling of adverse events in patients randomized to losartan treatment compared with β-blockers, suggesting that this study was underpowered to assess adverse aortic outcomes. On the other hand, the evidence for β-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective randomized and nonblinded clinical trial. Conclusions and Relevance Taken together, these data emphasize the need for clinical trials adequately powered to assess both aortic aneurysm growth and adverse aortic outcomes to identify effective medical therapies for Marfan syndrome and other aortopathies.

Enzyme modified non-oxidative LDL (ELDL) is effectively taken up by vascular smooth muscle cells (SMC) and mediates transition into foam cells and produces phenotypic changes in SMC function. Our data show that incubation of human coronary artery SMC (HCASMC) with low concentration of ELDL (10 μg/ml) results in significantly enhanced foam cell formation compared to oxidized LDL (200 μg/ml; p

BACKGROUND: Atrial fibrillation (AF) is associated with death in patients with chronic kidney disease (CKD). We examined the associations between AF and cause-specific mortality in a large CKD population. METHODS: We included 62,459 patients with eGFR 15–59 ml/min/1.73 m(2) (6,639 patients with AF and 55,820 without AF) followed in a large health care system. Outcomes included overall and cause-specific deaths (a) cardiovascular; b) malignancy; and c) non-cardiovascular/non-malignancy causes). Cox regression models for overall mortality and separate competing risk models for each major cause of death category were used to evaluate their respective associations with AF. RESULTS: During a median follow-up of 4.1 years, 19,094 patients died; cause of death was available for 18,854 patients. After multivariable adjustment (demographics, comorbidities, relevant laboratory data, medication use and kidney function), AF was associated with 23% (95% CI: 18%−29%) higher risk of all-cause mortality, 45% (95% CI: 31%−61%) higher risk of cardiovascular mortality and 13% (95% CI: 3%−22%) lower risk of malignancy-related mortality Exclusion of patients with malignancy yielded similar results except for a lack of association between AF and malignancy-related deaths. Results were consistent across various stages of CKD. CONCLUSIONS: In a non-dialysis dependent CKD population, presence of AF was associated with higher all-cause and cardiovascular mortality. These data suggest that patients with both CKD and AF are at high cardiovascular risk, and thus clinical practice (or trials) should aim at reducing the overall excess cardiovascular mortality (not stroke alone) in patients with AF and CKD.

© 2014 American Heart Association, Inc. Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.

A 55 year-old male with a history of erosive, seropositive rheumatoid arthritis (RA) and interstitial lung disease (ILD) presented with shortness of breath. Echocardiography showed new onset severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 15%, moderately increased mean aortic valve gradient of 20 mmHg in a tri-leaflet aortic valve with severe sclero-calcific degeneration. Coronary angiography revealed no significant obstructive coronary disease. Invasive hemodynamic studies and dobutamine stress echocardiography were consistent with moderate aortic stenosis. Guideline directed medical therapy for heart failure with reduced ejection fraction (HFrEF) was initiated, however diuretics and neurohormonal blockade (beta blocker and angiotensin receptor blocker) provided minimal improvement and the patient remained functionally limited. Of interest, echocardiography performed one year prior to his presentation showed normal LV EF and mild aortic leaflet calcification with moderate stenosis, suggesting a rapid progressing of calcific aortic valve disease. Subsequently, the patient underwent surgical aortic valve replacement (sAVR) and demonstrated excellent post-surgical recovery of LV EF (55%). Calcific aortic valve disease is commonly associated with aging, bicuspid aortic valve, and chronic kidney disease. Pathophysiological mechanism for valvular calcification are incompletely understood, but include osteogenic transformation of valvular interstitial cells mediated by local and systemic inflammatory processes. Several rheumatologic diseases including RA are associated with premature atherosclerosis and arterial calcification, and we speculated a similar role of RA accelerating calcific aortic valve disease. We present a case of accelerated aortic valve calcification with (only) moderate stenosis, complicated by a rapid decline in LV systolic performance. Guidelines for AVR in moderate stenosis without concomitant cardiac surgery are not well established, though it should be considered in selected patients.

Objective— S100A12 and fibroblast growth factor 23 are biomarkers of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. Approach and Results— A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9, and S100A12 was expressed in C57BL/6J mouse (hBAC-S100) to generate a novel humanized mouse model. CKD was induced by ureteral ligation, and hBAC-S100 mice and wild-type mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased fibroblast growth factor 23 in the hearts, left ventricular hypertrophy, diastolic dysfunction, focal cartilaginous metaplasia, and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in wild-type mice with CKD or in hBAC-S100 mice lacking the receptor for advanced glycation end products with CKD, suggesting that the inflammatory milieu mediated by S100/receptor for advanced glycation end products promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including interleukin-6, tumor necrosis factor-α, lipopolysaccarides, or serum from hBAC-S100 mice upregulated fibroblast growth factor 23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Conclusions— Myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a receptor for advanced glycation end products–dependent manner in a mouse model of CKD. We speculate that fibroblast growth factor 23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate left ventricular hypertrophy and diastolic dysfunction in hBAC-S100 mice with CKD.

There is an emerging widespread interest in the role of damage-associated molecular pattern molecules (DAMP) S100A8, S100A9 and S100A12 in cardiovascular and other diseases. In this study we tested the efficacy of ABR-215757, a S100 protein binding immuno-modulatory compound to stabilize atherosclerosis in transgenic ApoE null mice that express the human pro-inflammatory S100A12 protein within the smooth muscle cell (SM22α-S100A12).Twelve-week old S100A12 transgenic/ApoE(-/-) and WT/ApoE(-/-) mice were treated with ABR-21575 for 5 weeks and were analyzed 4 month later.Surface plasmon resonance analysis demonstrated that S100A12 interacts with ABR-215757 in a zinc dependent manner in vitro. In vivo, ABR-215757 administration reduced features of advanced plaque morphology resulting in smaller necrotic cores, diminished intimal and medial vascular calcification, and reduced amount of infiltrating inflammatory cells. ABR-215757 normalized aortic expression of RAGE protein and normalized experimentally-induced delayed hypersensitivity. The effect of ABR-215757 was more prominent in ApoE(-/-) mice expressing S100A12 than in ApoE(-/-) animals lacking expression of human S100A12 protein.Our data suggest that S100A12 is important for progression of atherosclerosis and can be targeted by the small molecule ABR-215757. The specific binding of quinoline-3-carboxamides to S100A12 attenuates S100A12-mediated features of accelerated murine atherosclerosis.

ObjectivesThe objective of this study was to examine the similarities and differences in Caucasian (C) and African-American (AA) patients with bicuspid aortic valve (BAV) with respect to morphology, severity of aortic stenosis/insufficiency, and aortic dilation.BackgroundBAV is a common congenital valve abnormality, accounting for a large number of valve replacements.MethodsA total of 229 patients with the diagnostic code BAV were identified retrospectively from our computerized adult echocardiographic database, which consists of 91,896 studies performed at the University of Chicago Medical Center from 1998 to 2009, representing 40,878 patients. Of those, 183 patients with BAV were included in this retrospective BAV single-center cohort study and reanalyzed with a comprehensive assessment of aortic dimensions, aortic valve morphology and function, clinical cardiovascular risk factors, and patient characteristics.ResultsOf the 183 patients with BAV, 138 were C and 45 were AA. Our echocardiographic database encompasses approximately 65% AA, 31% C, and 4% other races, for an estimated frequency of BAV in AA patients of 0.17% and a frequency in C patients of 1.1% (p = 0.001). There were no significant inter-racial differences regarding sex, height, weight, hyperlipidemia, diabetes, tobacco use, cardiac medications, and left ventricular ejection fraction. The AA cohort was older (age 50 ± 17 years vs. 43 ± 17 years, p < 0.05) and had a higher prevalence of hypertension (51% vs. 24%, p < 0.05). After adjusting for comorbidities, aortic dimensions were larger in C (C vs. AA: annulus, 2.4 ± 0.4 vs. 2.1 ± 0.4 cm; sinuses of Valsalva, 3.4 ± 0.7 vs. 3.1 ± 0.6 cm; sinotubular junction, 3.0 ± 0.6 vs. 2.6 ± 0.5 cm; and ascending aorta, 3.5 ± 0.7 vs. 3.2 ± 0.5 cm; all p values

The measurement of cardiac troponins (cTn) is widely used to diagnose myocardial injury or necrosis 1, 2 , and has become an important tool for the risk stratification and clinical management of patients with acute coronary syndrome (ACS) 3, 4 . However, elevated cTn levels are also found in non-ACS patients 5 . For example, in a recent study of patients with chronic stable coronary artery disease, higher cTn levels were observed in patients with concomitant kidney disease or diabetes mellitus 6, 7 . Furthermore, approximately 15% of patients with acute ischemic stroke have elevated cTn 8-11 ; many of whom, have no other clinical manifestation of acute coronary ischemia. Because cTn still provides important prognostic information regarding mortality outcomes in stroke patients 12 , current AHA guidelines recommend its measurement in all patients presenting with acute ischemic stroke 13 . However, the role of cTn in predicting culprit or obstructive coronary lesions in these patients remains unknown, but may be important to ascertain if subsequent revascularization therapy could be shown to be beneficial.

Elevated cardiac troponin (cTn) signals myocardial necrosis and injury but does not specify the mechanism of that injury. The measurement of cardiac troponins is widely used to diagnose myocardial infarction and has become an important tool for the risk stratification and clinical management of patients with acute coronary syndrome

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell–targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.

Objective— Enzyme-modified nonoxidized low-density lipoprotein (ELDL) is present in human atherosclerotic lesions. Our objective is to understand the mechanisms of ELDL uptake and its effects on vascular smooth muscle cells (SMC). Approach and Results— Transformation of murine aortic SMCs into foam cells in response to ELDL was analyzed. ELDL, but not acetylated or oxidized LDL, was potent in inducing SMC foam cell formation. Inhibitors of macropinocytosis (LY294002, wortmannin, amiloride) attenuated ELDL uptake. In contrast, inhibitors of receptor-mediated endocytosis (dynasore, sucrose) and inhibitor of caveolae-/lipid raft–mediated endocytosis (filipin) had no effect on ELDL uptake in SMC, suggesting that macropinocytosis is the main mechanism of ELDL uptake by SMC. Receptor for advanced glycation end products (RAGE) is not obligatory for ELDL-induced SMC foam cell formation, but primes SMC for the uptake of oxidized LDL in a RAGE-dependent manner. ELDL increased intracellular reactive oxygen species, cytosolic calcium, and expression of lectin-like oxidized LDL receptor-1 in wild-type SMC but not in RAGE −/− SMC. The macropinocytotic uptake of ELDL is regulated predominantly by intracellular calcium because ELDL uptake was completely inhibited by pretreatment with the calcium channel inhibitor lacidipine in wild-type and RAGE −/− SMC. This is in contrast to pretreatment with PI3 kinase inhibitors which completely prevented ELDL uptake in RAGE −/− SMC, but only partially in wild-type SMC. Conclusions— ELDL is highly potent in inducing foam cells in murine SMC. ELDL endocytosis is mediated by calcium-dependent macropinocytosis. Priming SMC with ELDL enhances the uptake of oxidized LDL.

Rationale:S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear.Objective:To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22α promoter because S100A12 is not present in mice.Methods and Results:Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor β pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells.Conclusions:S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.

Arterial inflammation is the consequence of an orchestrated response of cells within the arterial wall to multifactorial modes of injury; arterial inflammation is a fundamental mechanism contributing to atherosclerosis and restenosis. The remodeling of the arterial wall that results from the inflammation could either be obstructive (as in coronary and peripheral artery disease, or in-stent restenosis) or aneurysmal (as in thoracic and abdominal aortic aneurysms). It remains quite a challenge to decipher the distinct differences in local factors that lead to the varied possible outcomes of arterial inflammation. As a result, often we can’t fully explain the predilection to arterial inflammation of distinct vascular beds, or why, for example, obstruction occurs over dilatation. Atop these considerations, there is overwhelming evidence that arterial inflammation is also a systemic process. Indeed, it is remarkable that although the initial description of atherosclerosis as an inflammatory disease was suggested nearly two decades ago [1], the first large clinical trial directly testing the inflammation hypothesis was launched only very recently. Specifically, the “Cardiovascular Inflammation Reduction Trial (CIRT)” will randomize 7,000 patients with prior myocardial infarction and either diabetes or metabolic syndrome to low dose methotrexate or placebo. No doubt, the results of this pivotal trial will teach us important biology, and possibly irrevocably alter the means by which we treat patients with coronary artery disease [2]. In the context of common pathways mediating arterial inflammation, the Receptor for Advanced Glycation Endproducts (RAGE), is certainly a strong candidate molecule. Emerging evidence links RAGE to the pathogenesis of vascular inflammation [3]. RAGE is expressed in vascular endothelial cells, smooth muscle cells, and immune cells and transduces the signals of ligands such as advanced glycation endproducts (AGEs), pro-inflammatory S100/calgranulins, and high mobility group box 1 (HMGB1); these ligands have been localized to atherosclerotic and restenotic tissues. Further, RAGE is one of a family of receptors for lysophosphatidic acid (LPA) (Figure 1). AGEs are a diverse group of compounds that are generated through non-enzymatic glycation or glycoxidations of proteins, lipids and nucleic acids with the reactive carbonyl methylglyoxal considered as a major AGE precursor. AGE formation is directly accelerated by hyperglycemia and oxidative stress, but occurs also in normoglycemia during inflammation and oxidative stress. AGEs continue to accumulate in plasma and in tissues during natural aging. Other RAGE-ligands, including S100/calgranulins, HMGB1 and LPA are released from various cells during cell stress and injury and are indicators of cell damage. These ligands are therefore also known as “alarmins” or “damage associated-molecular pattern molecules” (DAMPs) and are important activators of innate immune responses [4]. S100/calgranulins are endogenous proteins in the cytosol of myeloid cells, particular in granulocytes, and are released upon cell activation. In addition, S100/calgranulins are up-regulated in smooth muscle and endothelial cells under pathological conditions, including acute myocardial infarction or aortic dissections [5]. Although heterogeneous in structure, these ligands commonly activate RAGE, which results in many downstream effects, including activation of adapter proteins, kinases, production of cytokines, adhesion molecules, migration and proliferation of smooth muscle cells that collectively contribute to arterial inflammation. For example, transgenic expression of S100A12 in the vascular smooth muscle of apoE deficient mice vastly accelerates atherosclerosis with enhanced formation of a necrotic core and other features commonly associated with vulnerable plaques (Figure 2) [6]. Therefore, blocking the activation of RAGE should dampen arterial inflammation. Indeed, studies in ApoE deficient mice with genetic ablation of RAGE revealed a reduction of vascular inflammation and early atherosclerosis and provided important experimental evidence that RAGE is a suitable target for therapeutic interventions [7]. Figure 1 Ligand-mediated activation of the Receptor for Advanced Glycation Endproducts (RAGE) mediates acute and sustained inflammation. Various ligands of RAGE, including Advanced Glycation Endproducts (AGEs), high mobility group protein box 1 (HMGB1), S100/calgranulins ... Figure 2 Advanced remodeling with necrotic core, elastic fiber degradation, and calcification in atherosclerotic plaques of the innominate artery in apoE deficient mice with transgenic expression of hS100A12 targeted to the vascular smooth muscle and in wildtype ... What about clinical application? In fact, a step forward for potential clinical translation was the development of soluble RAGE, a recombinant protein composed of the ligand-binding domain that inhibits the axis of ligand/RAGE/arterial inflammation. Earlier studies showed that administration of soluble RAGE to rodents reduced atherosclerosis [8], particularly that accelerated by diabetes, and suppressed arterial wire injury-mediated neointimal proliferation [9] in other animal models. Indeed, these studies using soluble RAGE produced in insect cells provided the pivotal “proof of concept” linking ligation of RAGE ligands to protection against vascular perturbation. In this issue of the Journal of Molecular Medicine, Tae and colleagues extend those findings and present a new variation of recombinant soluble RAGE using the mammalian CHO cell line (Chinese hamster ovary) for production of sRAGE [10], in contrast to insect cells (Sf9 cells) that were previously used to generate sRAGE for injection into animal models [8, 9]. The endoplasmatic reticulum of mammalian cells adds N-linked glycans during protein translation, which after extensive modifications and trimmings, are important for the proper folding, oligomerization, transport and ultimately function of the proteins. Li and colleagues demonstrate that sRAGE-CHO displays important differences in N-glycans compared to sRAGE-Sf9, and this difference in post-translational modifications might possibly explain that a single dose of 3 ng/g body weight injected at the time of balloon angioplasty reduced neointimal hyperplasia by 70% in a rat carotid artery balloon injury model. N-Glycan modification within the ligand-binding-domain of RAGE was previously shown to increase the ligand-binding capacity of RAGE, particularly its binding to S100A12 [11]. This study by Tae and colleagues reinforces the concept that quenching RAGE-ligands that are in excess at the site of arterial injury using a small but very effective dose of sRAGE-CHO is an attractive avenue that should be further studied and possibly developed as a therapeutic protein applicable in multiple diseases linked to arterial inflammation. Finally, Tae and colleagues refer to “high” vs. “low” doses of insect cell vs. CHO cell-produced material [10]. It is essential to note that such definitions may not be relevant to the ultimate application to clinical practice, as Li and colleagues have not yet performed detailed pharmacokinetic testing with their newest version of soluble RAGE. Indeed, in the case of insect cell- or CHO cell-produced material, it is possible that local delivery of either agent directly at the site of percutaneous coronary intervention might be the most logical means to block the vascular perturbing properties of RAGE ligands in atherosclerosis and restenosis.

We report a case of congenital bicuspid aortic valve infective endocarditis in an 18-year-old male with no significant past medical history. He presented to the emergency department from an ophthalmology clinic with new right-eye vision changes. Initial EKG revealed sinus tachycardia and he was hemodynamically stable. Expedited diagnostic transesophageal echocardiography revealed vegetations on both aortic leaflets, an aortic root abscess, and a fistulous tract extending from the left ventricular outflow tract into the right ventricular outflow tract. Although he was evaluated by the cardiothoracic surgery team and scheduled for operative repair, he acutely became bradycardic, developed pulseless electrical activity, and was resuscitated on multiple occasions, but died suddenly from PEA arrest within 24 hours of presenting to the emergency department. This case demonstrates complications of acute bacterial endocarditis. We discuss the current debate surrounding the role of antibiotic prophylaxis for infective endocarditis. Additionally, we suggest that patients with a bicuspid aortic valve, a common congenital defect with a known increased risk for bacterial endocarditis, might represent a unique cohort to prospectively study whether antibiotic prophylaxis reduces the incidence, morbidity, and mortality of bacterial endocarditis in patients at increased risk.

Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD.This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia.hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNFα, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts.Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic dysfunction in hBAC-S100 mice with CKD. We suggest that S100/RAGE-mediated chronic sustained systemic inflammation is linked to pathological cardiac remodeling via direct up regulation of FGF23 in cardiac fibroblasts, thereby providing a new mechanistic understanding for the common association between CKD, diabetes, metabolic syndrome, or hypertension with left ventricular hypertrophy with diastolic dysfunction.

Airway inflammation, lung remodeling, and Airway Hyperresponsiveness (AHR) are major features of asthma and Chronic Obstructive Pulmonary Disease (COPD). The inflammatory response to allergens, air pollutants, and other insults is likely to play a key role in promoting structural changes in the lung including the overabundance of Airway Smooth Muscle (ASM) seen in asthmatics. These alterations or remodeling could, in turn, impact the immunmodulatory actions of the ASM, the ASM's contractile properties, and the development of AHR. New evidences suggest that airway inflammation and AHR are not tightly related to each other and that the structural component of the airway, mainly the ASM, is a chief driver of AHR. Members of the S100/calgranulins family have been implicated in the regulation of inflammation and cell apoptosis in various systems. S100A12 is highly expressed in neutrophils and is one of the most abundant proteins in the lungs of patients with asthma or COPD. Studies with genetic engineered mice with smooth muscle cell-targeted expression of human S100A12 revealed that S100A12 reduces airway smooth muscle amounts and dampens airway inflammation and airway hyperreactivity in a model of allergic lung inflammation. Thus, targeting airway smooth muscle for instance through delivery of pro-apoptotic S100A12 could represent an attractive means to promote ASM apoptosis and to reduce ASM abundance in asthmatics.

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

Background: ELDL is present in human atherosclerotic lesions and promotes foam cell formation in cultured macrophages and vascular smooth muscle cells (SMC). Here we study mechanism of ELDL uptake and its effects on SMCs. Methods and Results: Incubation of wild type murine aortic SMCs with 10 μg/ml ELDL (trypsin, cholesterol esterase modified) results in enhanced foam cell formation (analyzed by Oil Red O, lipid measurement) compared to SMCs incubated with acetylated LDL (500 μg/ml; -50%, p Conclusions: ELDL is highly potent in inducing foam cells in aortic SMCs. ELDL endocytosis is mediated by RAGE-regulated, Ca2+ dependent macropinocytosis.

Background: Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. Methods: This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. Results: hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNF, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Conclusions: Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic dysfunction in hBAC-S100 mice with CKD. We suggest that S100/RAGE-mediated chronic sustained systemic inflammation is linked to pathological cardiac remodeling via direct up regulation of FGF23 in cardiac fibroblasts, thereby providing a new mechanistic understanding for the common association between CKD, diabetes, metabolic syndrome, or hypertension with left ventricular hypertrophy with diastolic dysfunction.

IL22 belongs to the IL10 cytokine family and is expressed by T helper cells. IL22 functions on epithelial cells and has been shown to improve epithelial barrier function in inflammatory bowel disease, asthma, and psoriasis; autoimmune diseases associated with elevated serum IL22. Patients with psoriasis have increased coronary artery disease and it was previously shown that macrophages from patients with psoriasis have impaired cholesterol efflux. The function of IL-22 on macrophage cholesterol metabolism is not known. Methods: ABCA1, ABCG1 and CD36 mRNA and protein expression, cholesterol uptake and efflux were studied in murine macrophages and human THP-1 macrophages. C57BL6/J mice with transgenic expression of hS100A12 and hS100A8/9 in myeloid cells were generated by using a bacterial artificial chromosome (hBAC/S100 mice). hBAC/S100 and WT littermate mice were breed into mice lacking the receptor for advanced glycation endproducts, RAGE. Results: Peritoneal macrophages from hBAC/S100 mice have reduced ABCG1 mRNA and protein expression, increased cholesterol uptake, and reduced cholesterol efflux compared to WT. This was abolished in hBAC/S100 mice lacking RAGE, the receptor for S100/calgranulin. Recombinant S100A12 or S100A8 protein (2.5 μg/ml) had no effect on ABCG1 expression in WT peritoneal macrophages or human THP-1 cells, suggesting other systemic intermediary products in hBAC/S100 mice. Serum IL22 and mRNA in splenic T cells were significantly increased in hBAC/S100 mice, and this was abolished in hBAC/S100 mice lacking RAGE. Moreover, r S100A12 increased IL22 mRNA by 2-fold in cultured human THP-1. Importantly, THP-1 macrophages treated with r IL22 (100 ng/ml) had reduced expression of ABCG1 and impaired cholesterol efflux to mouse serum, but not to Apoa1. Up regulation of ABCG1 and ABCA1 in response to LXR agonist TO901317 in THP-1 cells abolished the detrimental effects of IL22 on cholesterol efflux. Conclusion: S100/calgranulin induces IL22 in a RAGE dependent manner. IL22 down regulates ABCG1 and impairs cholesterol efflux in macrophages. This raises the hypothesis that IL22-mediated down regulation of cellular cholesterol efflux may be linked to improved epithelial barrier function, but may also augment atherosclerosis.

Study’s purpose: Plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) and S100A12 are increased in young children after cardiac surgery and correlate with the time spent on cardiopulmonary bypass (CPB). This study was performed to investigate whether plasma levels of sRAGE and S100A12 are affected by the use of CPB. Levels of S100A12 and sRAGE, along with of interleukin-6, tumor necrosis factor-α, myeloperoxidase, and C-reactive protein were measured in 25 adults undergoing non-urgent coronary artery bypass grafting with and without the use of CPB. Significant finding: Plasma levels of S100A12, sRAGE, IL-6, TNF-α and MPO 4h after cardiac surgery were elevated compared to baseline; this increase was equally observed in patients undergoing traditional coronary artery bypass grafting on cardiopulmonary bypass (n = 16), and in patients undergoing robot-assisted coronary artery bypass grafting off pump (OPCAB, n = 9). Patients with prolonged hospitalization of 7 days or longer had significantly higher S100A12 and sRAGE 4 hours post surgery compared to patients hospitalized ≤ 6 days. Conclusion: Increased sRAGE and S100A12 after cardiac surgery is associated with prolonged length of hospitalization in patients after coronary artery bypass grafting; however, we did not observe an intrinsic effect of cardiopulmonary bypass on S100A12 or sRAGE plasma levels in our small pilot study. Further studies are required to confirm the value of sRAGE and S100A12 in predicting postoperative complications after cardiac surgery in a larger study.

Purpose: Circulating serum levels of human S100/calgranulins have been associated with diabetes, coronary artery disease and increased cardiovascular mortality in clinical studies. To test whether S100/calgranulins are biomarker of inflammation or directly mediate disease, we exploited the fact that mice lack the gene for S100A12, and generated a novel humanized mouse with transgenic expression of human S100/calgrnaulin. Methods: hBAC-S100 mice were generated in C57BL6/J mice by expression of a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing genes and regulatory elements for S100A8/9 and S100A12 (60kb). F3 animals and wild type (WT) control littermate mice were maintained in pathogen free barrier facility with free access to water and regular rodent chow diet and studied at age 1, 3 and 12 months. Results: S100A12 protein is expressed in myeloid circulating blood cells and present in the serum of hBAC-S100 mice (25 ng/ml serum), but was not detected in WT mice. BAC-S100 mice developed normal and showed marked increase in visceral adiposity at 12 months upon DEXA scanning (25% vs 12%, p Conclusion: Circulating myeloid derived human S100/calgranulin is sufficient to induce a sustained inflammatory state and is associated with the development of adiposity, hyperinsulinemia, impaired glucose tolerance and aortic valve calcification in chow fed C57BL6 mice.

Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification.

Atherosclerosis remains the leading cause of death in the western countries and represents a complex chronic inflammatory process whose regulation is dependent on a network of cytokine and chemokine signaling between key cells such as endothelial cells, monocytes, dendritic cells, lymphocytes and smooth muscle cells. This review focuses on the biology and function of S100 proteins and their receptor RAGE with respect to the multifactorial process leading to atherosclerosis, plaque rupture, and aortic wall remodeling.

Advanced glycation end products (AGEs) are chemically heterogeneous structures and include such specific forms as carboxy (methyl)lysine, pentosidine and others, and were previously measured in heart failure patients as serum AGE, skin AGE, and AGE in cardiomyocytes and vascular cells within the heart. The study by Nozynski et al.1 adds to this body of knowledge as it examines AGE expression directly in explanted hearts: 22 with cardiomyopathy (CMP) and diabetes (DM), 114 with CMP without DM, 20 healthy heart donors, and 14 with DM without CMP. One of the main findings in this study was equally increased AGE accumulation in intramyocardial veins, arterioles and venules in diabetic subjects with and without CMP. This is an unexpected finding, since it is believed that AGE may contribute to mechanical (stiffness) as well as molecular (inflammation) changes contributing to myocardial dysfunction. However, we would like to offer a hypothesis for this unexpected result not raised by the authors. The diabetic cohort without CMP consists of patients who died in the first 24 hours after admission to the intensive care unit due to cerebral injury, and therefore represent a very sick cohort. It is well established that trauma is associated with a high burden of systemic inflammation, oxidative stress and for instance serum myeloperoxidase activity is highest in the first 6 hours in non-surviving patients with head trauma2. Moreover, inflammation, reactive oxygen species and myeloperoxidase enzymatic activity promotes protein glycation and AGE formation as rapidly as in 60 minutes3. AGE formation in human tissue is a dynamic process as recently demonstrated by the rapid decline of AGEs in myeloperoxidase-positive inflammatory cells in carotid endarterectomy tissue after treatment with simvastatin prior to surgery4. We speculate that the increased accumulation of AGE in the heart of diabetic subjects without CMP found in the study by Nozynski et al. may be largely explained by the circumstances of this study. The authors cannot exclude the possibility of rapid AGEs formation as a result of enhanced oxidative stress and myeloperoxidase activity associated with lethal trauma in this diabetic control group without CMP. Further studies examining AGE in cardiac tissue are needed to dissect the role of AGE in heart failure. Most importantly, more in-depth analysis of the specific AGEs and their concentrations in these tissues must be performed. Indeed, the concept of the heterogeneous nature of AGEs is underscored in Nyzynski’s study population and design.