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Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies feature fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and often differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways for potential development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease. Statement of significance Mitral valve disease is a common cardiovascular condition that is often accompanied by fibrotic tissue remodeling. Valvular interstitial cells (VICs), the fibroblast-like cells that reside in heart valve leaflets, are thought to drive fibrosis during valve disease by differentiating into activated myofibroblasts. However, the signaling pathways that regulate this process in the mitral valve are not fully understood. In the present study, we cultured mitral VICs in collagen and poly(ethylene glycol) scaffolds designed to mimic the heart valve microenvironment and treated the cell-seeded scaffolds with cytokines. Using these 3D culture models, we found that the pro-inflammatory cytokines TNF-α and IL-1β downregulate myofibroblast and fibrosis markers in mitral VICs via the canonical NF-κB signaling pathway.

PURPOSE. Discrete subaortic stenosis (DSS) is a left-ventricular outflow tract (LVOT) obstruction caused by a membranous lesion. DSS is associated with steep aortoseptal angles (AoSAs) and is a risk factor for aortic regurgitation (AR). However, the etiology of AR secondary to DSS remains unknown. This study aimed at quantifying computationally the impact of AoSA steepening and DSS on aortic valve (AV) hemodynamics and AR. METHODS. An LV geometry reconstructed from cine-MRI data was connected to an AV geometry to generate a unified 2D LV-AV model. Six geometrical variants were considered: unobstructed (CTRL) and DSS-obstructed LVOT (DSS), each reflecting three AoSA variations (110°, 120°, 130°). Fluid-structure interaction simulations were run to compute LVOT flow, AV leaflet dynamics, and regurgitant fraction (RF). RESULTS. AoSA steepening and DSS generated vortex dynamics alterations and stenotic flow conditions. While the CTRL-110° model generated the highest degree of leaflet opening asymmetry, DSS preferentially altered superior leaflet kinematics, and caused leaflet-dependent alterations in systolic fluttering. LVOT steepening and DSS subjected the leaflets to increasing WSS overloads (up to 94% increase in temporal shear magnitude), while DSS also increased WSS bidirectionality on the inferior leaflet belly (+0.30-point in oscillatory shear index). Although AoSA steepening and DSS increased diastolic transvalvular backflow, regurgitant fractions (RF

Objective Abnormal pulmonary vasculature directly affects the development and progression of congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH). Though overarching structural and cellular changes in CDH-affected pulmonary arteries have been documented, the precise role of the extracellular matrix (ECM) in the pulmonary artery (PA) pathophysiology remains undefined. Here, we quantify the structural, compositional, and mechanical CDH-induced changes in the main and distal PA ECM and investigate the efficacy of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a therapy to ameliorate pathological vascular ECM changes. Methods Pregnant Sprague-Dawley rodents were administered nitrofen to induce CDH-affected pulmonary vasculature in the offspring. A portion of CDH-affected pups was treated with intravenous infusion of MSC-EVs (1 × 1010 /mL) upon birth. A suite of histological, mechanical, and transmission electron microscopic analyses were utilized to characterize the PA ECM. Results The CDH model main PA presented significantly altered characteristics-including greater vessel thickness, greater lysyl oxidase (LOX) expression, and a relatively lower ultimate tensile strength of 13.6 MPa compared to control tissue (25.1 MPa), suggesting that CDH incurs ECM structural disorganization. MSC-EV treatment demonstrated the potential to reverse CDH-related changes, particularly through rapid inhibition of ECM remodeling enzymes (LOX and MMP-9). Additionally, MSC-EV treatment bolstered structural aspects of the PA ECM and mitigated pathological disorganization as exhibited by increased medial wall thickness and stiffness that, while not significantly altered, trends away from CDH-affected tissue. Conclusions These data demonstrate notable ECM remodeling in the CDH pulmonary vasculature, along with the capacity of MSC-EVs to attenuate pathological ECM remodeling, identifying MSC-EVs as a potentially efficacious therapeutic for CDH-associated pulmonary hypertension.

This paper provides a synopsis of discussions related to biomedical engineering core curricula that occurred at the Fourth BME Education Summit held at Case Western Reserve University in Cleveland, Ohio in May 2019. This summit was organized by the Council of Chairs of Bioengineering and Biomedical Engineering, and participants included over 300 faculty members from 100+ accredited undergraduate programs. This discussion focused on six key questions: QI: Is there a core curriculum, and if so, what are its components? QII: How does our purported core curriculum prepare students for careers, particularly in industry? QIII: How does design distinguish BME/BIOE graduates from other engineers? QIV: What is the state of engineering analysis and systems-level modeling in BME/BIOE curricula? QV: What is the role of data science in BME/BIOE undergraduate education? QVI: What core experimental skills are required for BME/BIOE undergrads? s. Indeed, BME/BIOI core curricula exists and has matured to emphasize interdisciplinary topics such as physiology, instrumentation, mechanics, computer programming, and mathematical modeling. Departments demonstrate their own identities by highlighting discipline-specific sub-specialties. In addition to technical competence, Industry partners most highly value our students' capacity for problem solving and communication. As such, BME/BIOE curricula includes open-ended projects that address unmet patient and clinician needs as primary methods to prepare graduates for careers in industry. Culminating senior design experiences distinguish BME/BIOE graduates through their development of client-centered engineering solutions to healthcare problems. Finally, the overall BME/BIOE curriculum is not stagnant-it is clear that data science will become an ever-important element of our students' training and that new methods to enhance student engagement will be of pedagogical importance as we embark on the next decade.

Congenital heart disease (CHD) poses a significant global health and economic burden—despite advances in treating CHD reducing the mortality risk, globally CHD accounts for approximately 300,000 deaths yearly. Children with CHD experience both acute and chronic cardiac complications, and though treatment options have improved, some remain extremely invasive. A challenge in addressing these morbidity and mortality risks is that little is known regarding the cause of many CHDs and current evidence suggests a multifactorial etiology. Some studies implicate an immune contribution to CHD development; however, the role of the immune system is not well-understood. Defining the role of the immune and inflammatory responses in CHD therefore holds promise in elucidating mechanisms underlying these disorders and improving upon current diagnostic and treatment options. In this review, we address the current knowledge coinciding CHDs with immune and inflammatory associations, emphasizing conditions where this understanding would provide clinical benefit, and challenges in studying these mechanisms.

Children with acquired heart disease face significant health challenges, including a lifetime of strict medical management, multiple cardiac surgeries, and a high mortality risk. Though the presentation of these conditions is diverse, a unifying factor is the role of immune and inflammatory responses in their development and/or progression. For example, infectious agents have been linked to pediatric cardiovascular disease, leading to a large health burden that disproportionately affects low-income areas. Other implicated mechanisms include antibody targeting of cardiac proteins, infection of cardiac cells, and inflammation-mediated damage to cardiac structures. These changes can alter blood flow patterns, change extracellular matrix composition, and induce cardiac remodeling. Therefore, understanding the relationship between the immune system and cardiovascular disease can inform targeted diagnostic and treatment approaches. In this review, we discuss the current understanding of pediatric immune-associated cardiac diseases, challenges in the field, and areas of research with potential for clinical benefit.

Calcific aortic valve disease (CAVD) is the most common heart valve disease requiring intervention. Most research on CAVD has focused on inflammation, ossification, and cellular phenotype transformation. To gain a broader picture into the wide range of cellular and molecular mechanisms involved in this disease, we compared the total protein profiles between calcified and non-calcified areas from 5 human valves resected during surgery. The 1413 positively identified proteins were filtered down to 248 proteins present in both calcified and non-calcified segments of at least 3 of the 5 valves, which were then analyzed using Ingenuity Pathway Analysis. Concurrently, the top 40 differentially abundant proteins were grouped according to their biological functions and shown in interactive networks. Finally, the abundance of selected osteogenic proteins (osteopontin, osteonectin, osteocalcin, osteoprotegerin, and RANK) was quantified using ELISA and/or immunohistochemistry. The top pathways identified were complement system, acute phase response signaling, metabolism, LXR/RXR and FXR/RXR activation, actin cytoskeleton, mineral binding, nucleic acid interaction, structural extracellular matrix (ECM), and angiogenesis. There was a greater abundance of osteopontin, osteonectin, osteocalcin, osteoprotegerin, and RANK in the calcified regions than the non-calcified ones. The osteogenic proteins also formed key connections between the biological signaling pathways in the network model. In conclusion, this proteomic analysis demonstrated the involvement of multiple signaling pathways in CAVD. The interconnectedness of these pathways provides new insights for the treatment of this disease.

Radiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space radiation on the cardiovascular system, as an increasing number of astronauts will be exposed to space radiation for longer periods of time. Research has shown that exposure to different types of particles found in space radiation can lead to the development of diverse cardiovascular disease via fibrotic myocardial remodeling, accelerated atherosclerosis and microvascular damage. Several underlying mechanisms for radiation-induced cardiovascular disease have been identified, but many aspects of the pathophysiology remain unclear. Existing pharmacological compounds have been evaluated to protect the cardiovascular system from space radiation-induced damage, but currently no radioprotective compounds have been approved. This review critically analyzes the effects of space radiation on the cardiovascular system, the underlying mechanisms and potential countermeasures to space radiation-induced cardiovascular disease.

Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies demonstrate a pronounced degree of fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and show a tendency to differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways that could enable the development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease.

This study documents perceptions of the relative harmfulness of marijuana and alcohol to a person's health among adults in Oregon just before the first legal sales of marijuana for recreational use. We surveyed 1941 adults in Oregon in September 2015. Respondents were recruited using an address-based sampling (ABS) frame (n = 1314) and social media advertising (n = 627). Respondents completed paper surveys (ABS-mail, n = 388) or online surveys (ABS-online, n = 926; social media, n = 627). We used descriptive statistics and logistic regression models to examine perceptions of the relative harmfulness of marijuana and alcohol by sample characteristics, including substance use. About half of adults in Oregon (52.5%) considered alcohol to be more harmful to a person's health than marijuana. A substantial proportion considered the substances equally harmful (40.0%). Few considered marijuana to be more harmful than alcohol (7.5%). In general, respondents who were younger, male, and not Republican were more likely than others to consider alcohol more harmful than marijuana. Respondents who were older, female, and Republican were more likely to consider marijuana and alcohol equally harmful. Most individuals who reported using both marijuana and alcohol (67.7%) and approximately half of those who used neither substance (48.2%) considered alcohol to be more harmful than marijuana. Perceptions about the relative harmfulness of marijuana and alcohol may have implications for public health. As state lawmakers develop policies to regulate marijuana, it may be helpful to consider the ways in which those policies may also affect use of alcohol and co-use of alcohol and marijuana.

Heart valve tissue engineering is emerging as a promising method for constructing both valve replacements and valvular disease models. Tissue-engineered valve replacements strive to overcome the limitations of mechanical and bioprosthetic valves, because they are living tissues capable of active remodeling and self-repair. Several tissue-engineered valve replacements have displayed promising results in recent large-animal trials. On the other hand, tissue-engineered disease models provide a scalable platform for investigating the pathobiology of valvular diseases like aortic stenosis. Recently, these models have been used to study the role of spatial heterogeneity, temporal matrix stiffening, and inter-cellular signaling in valve disease. This review provides an overview of recent developments, current challenges, and future directions in the field of heart valve tissue engineering.

Objective: Discrete subaortic stenosis (DSS) is a left-ventricular outflow tract (LVOT) obstruction caused by a membranous lesion. DSS is commonly associated with steep aortoseptal angles (AoSAs) a...

This study examines the relationships between trial of new marijuana or hashish products and unexpected highs, and use of edible products and unexpected highs.We conducted an online survey of 634 adult, past-year marijuana users in Colorado. We used logistic regression models to examine the relationship between new product trial or edible use and unexpected highs.In the first year that recreational marijuana was legal in Colorado, 71.4% of respondents tried a new marijuana or hashish product, and 53.6% used an edible product. Trial of new products was associated with greater odds of experiencing an unexpected high after controlling for age, gender, education, mental health status, current marijuana or hashish use, and mean amount of marijuana or hashish consumed in the past month (OR=2.13, p0.001). Individuals who reported having used edibles had greater odds of experiencing an unexpected high, after controlling for the same set of variables (OR=1.56, p0.05).People who try new marijuana or hashish products, or use edible marijuana or hashish products, are at greater risk for an unexpected high. It is possible that some negative outcomes associated with marijuana use and unexpected highs may be averted through a better understanding of how to use product packaging to communicate with consumers.

Three-dimensional (3D) printing is an advanced manufacturing technique, recently introduced in the medical field to convert clinical imaging information of anatomical features into physical replica...

Objective: Aortic valve disease is commonly found in the elderly population. It is characterized by dysregulated extracellular matrix remodeling followed by extensive microcalcification of the aortic valve and activation of valve interstitial cells. The mechanism behind these events are largely unknown. Studies have reported expression of hypoxia inducible factor-1 alpha (HIF1α) in calcific nodules in aortic valve disease, therefore we investigated the effect of hypoxia on extracellular matrix remodeling in aged aortic valves. Approach and Results: Western blotting revealed elevated expression of HIF1α and the complex of matrix metalloprotease 9 (MMP9) and neutrophil gelatinase-associated lipocalin (NGAL) in aged porcine aortic valves cultured under hypoxic conditions. Consistently, immunofluorescence staining showed co-expression of MMP9 and NGAL in the fibrosa layer of these porcine hypoxic aortic valves. Gelatinase zymography demonstrated that the activity of MMP9-NGAL complex was significantly increased in aortic valves in 13% O2 compared to 20% O2. Importantly, the presence of ectopic elastic fibers in the fibrosa of hypoxic aortic valves, also detected in human diseased aortic valves, suggests altered elastin homeostasis due to hypoxia. Conclusion: This study demonstrates that hypoxia stimulates pathological extracellular matrix remodeling via expression of NGAL and MMP9 by valve interstitial cells.

Designing and constructing controlled in vitro cell culture platforms is imperative toward pinpointing factors that contribute to the development of calcific aortic valve disease. A 3D, laminar, filter paper-based cell culture system that was previously established as a method of analyzing valvular interstitial cell migration and protein expression was adapted here for studying the impact of specific extracellular matrix proteins on cellular viability and calcification proclivity. Hydrogels incorporating hyaluronan and collagen I, two prevalent valvular extracellular matrix proteins with altered pathological production, were designed with similar mechanics to parse out effects of the individual proteins on cell behavior. Laminar constructs containing varying combinations of discrete layers of collagen and hyaluronan were assembled to mimic native and pathological valve compositions. Proteinaceous and genetic expression patterns pertaining to cell viability and calcific potential were quantified via fluorescent imaging. A significant dose-dependency was observed, with increased collagen content associated with decreased viability and increased calcific phenotype. These results suggest that extracellular composition is influential in calcific aortic valve disease progression and will be key toward development of future tissue-engineered or pharmaceutical calcific aortic valve treatments. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD), a widespread heart valve disorder, is characterized by fibrotic leaflet thickening and calcific nodule formation. This pathological remodeling is an active process mediated by the valvular interstitial cells (VICs). Currently, the only treatment available is surgical replacement of the valve - a procedure associated with significant long-term risk and morbidity. Development of effective alternate therapies is hindered by our poor understanding of CAVD etiology. Previous work has implicated the composition and mechanics of the extracellular matrix in the progression of CAVD. These individual factors and their magnitude of influence have not been extensively explored - particularly in 3D systems. Here, we have bridged this gap in understanding through the employment of a heterogeneous 3D filter-paper culture system.

Calcification is a prevalent disease in most fully developed countries and is predominantly observed in heart valves and nearby vasculature. Calcification of either tissue leads to deterioration and, ultimately, failure causing poor quality of life and decreased overall life expectancy in patients. In valves, calcification presents as Calcific Aortic Valve Disease (CAVD), in which the aortic valve becomes stenotic when calcific nodules form within the leaflets. The initiation and progression of these calcific nodules is strongly influenced by the varied mechanical forces on the valve. In turn, the addition of calcific nodules creates localized disturbances in the tissue biomechanics, which affects extracellular matrix (ECM) production and cellular activation. In vasculature, atherosclerosis is the most common occurrence of calcification. Atherosclerosis exhibits as calcific plaque formation that forms in juxtaposition to areas of low blood shear stresses. Research in these two manifestations of calcification remain separated, although many similarities persist. Both diseases show that the endothelial layer and its regulation of nitric oxide is crucial to calcification progression. Further, there are similarities between vascular smooth muscle cells and valvular interstitial cells in terms of their roles in ECM overproduction. This review summarizes valvular and vascular tissue in terms of their basic anatomy, their cellular and ECM components and mechanical forces. Calcification is then examined in both tissues in terms of disease prediction, progression, and treatment. Highlighting the similarities and differences between these areas will help target further research toward disease treatment.

This study examines the relationship between self-reports of being high on marijuana and perceptions about driving high or drunk. Data were collected in 2014 from an online convenience sample of adult, past 30-day marijuana and hashish users in Colorado and Washington (n = 865). Respondents were asked, "Were you high or feeling the effects of marijuana or hashish when you took this survey?" Logistic regression was used to assess the relationship between being high and beliefs about driving high, controlling for demographics and marijuana use. Respondents who reported being high at the time of survey administration had higher odds of agreeing with the statements, "I can safely drive under the influence of marijuana" (OR = 3.13, P < 0.001) and "I can safely drive under the influence of alcohol" (OR = 3.71, P < 0.001) compared with respondents who did not report being high. Respondents who were high also had higher odds of being open to driving high under certain circumstances. Being high may influence perceptions about the safety of drugged and drunk driving. The effectiveness of public health messages to prevent drugged and drunk driving may depend in part on how persuasive they are among individuals who are high.

Discrete subaortic stenosis (DSS) is a congenital heart disease that results in the formation of a fibro-membranous tissue, causing an increased pressure gradient in the left ventricular outflow tract (LVOT). While surgical resection of the membrane has shown some success in eliminating the obstruction, it poses significant risks associated with anesthesia, sternotomy, and heart bypass, and it remains associated with a high rate of recurrence. Although a genetic etiology had been initially proposed, the association between DSS and left ventricle (LV) geometrical abnormalities has provided more support to a hemodynamic etiology by which congenital or post-surgical LVOT geometric derangements could generate abnormal shear forces on the septal wall, triggering in turn a fibrotic response. Validating this hypothetical etiology and understanding the mechanobiological processes by which altered shear forces induce fibrosis in the LVOT are major knowledge gaps. This perspective paper describes the current state of knowledge of DSS, articulates the research needs to yield mechanistic insights into a significant pathologic process that is poorly understood, and proposes several strategies aimed at elucidating the potential mechanobiological synergies responsible for DSS pathogenesis. The proposed roadmap has the potential to improve DSS management by identifying early targets for prevention of the fibrotic lesion, and may also prove beneficial in other fibrotic cardiovascular diseases associated with altered flow.

Rationale: The high prevalence of cardiovascular disease (CVD) in cancer survivors after ionizing radiation (IR) therapy has long been recognized, but the mechanism for this is unknown. Previous studies reported that the plaques in IR therapy survivors exhibit characteristics of increased instability without changes in the plaque size. Objective: To study the mechanism of IR induced CVD in humans, we decided to develop an IR mouse model that mimics human CV events. Methods and Results: We fed LDLR-/- mice or C57 mice with a single injection of adeno -associated virus vector(AAV) encoding a gain-of function of PCSK9 with a high fat diet, then irradiated the mice with different doses of IR (2 Gy, 5 Gy, 10 Gy). Whole body radiation was given 2 Gy, while localized IR to the neck and thoracic area was given at 5 Gy (1 time) or 10Gy (weekly 5 Gy, twice).About 2~3 weeks after the IR treatment, we performed left partial carotid artery ligation (PCL), and 3 weeks later examined the extent of plaque formation and cardiac abnormality by comparing those detected in non-irradiated control mice. The lesion area ratio between the partially ligated left carotid artery (LCA) and the right carotid artery (RCA) was significantly increased in the IR-treated group compared to the non-IR-treated group (3.1 ± 0.3 vs.1.8 ± 0.4, n = 7-8, p = 0.03). In addition, the lesion in the IR-treated of mice had significantly larger necrotic cores with a thinner fibrous cap when compared to those in non-irradiate mice. Furthermore, IR-treated mice showed cardiac hypertrophy, in which we found a significant increase of the wall thickness of mid-to small sized arteries as well as perivascular fibrosis, which were not noticed in the non-IR-treated mice. Conclusions: Our results demonstrate that IR not only increases atherosclerotic and vulnerable plaque formation but also cardiac hypertrophy with mid- and micro-vascular wall swelling. The increase of mid- and micro-vascular wall thickness may explain the heart failure preserved heart failure, which is observed in the majority of heart failure patients after IR treatment.

Background: The high incidence of cardiovascular events in cancer survivors has long been noted, but the mechanistic insights of cardiovascular toxicity of cancer treatments, especially for vessel diseases, remain unclear. It is well known that atherosclerotic plaque formation begins in the area exposed to disturbed blood flow, but the relationship between cancer therapy and disturbed flow in regulating plaque formation has not been well studied. Therefore, we had two goals for this study; 1) Generate an affordable, reliable, and reproducible mouse model to recapitulate the cancer therapy-induced cardiovascular events in cancer survivors, and 2) Establish a mouse model to investigate the interplay between disturbed flow and various cancer therapies in the process of atherosclerotic plaque formation. Methods and Results: We examined the effects of two cancer drugs and ionizing radiation (IR) on disturbed blood flow-induced plaque formation using a mouse carotid artery partial ligation (PCL) model of atherosclerosis. We found that doxorubicin and cisplatin, which are commonly used anti-cancer drugs, had no effect on plaque formation in partially ligated carotid arteries. Similarly, PCL-induced plaque formation was not affected in mice that received IR (2 Gy) and PCL surgery performed one week later. In contrast, when PCL surgery was performed 26 days after IR treatment, not only the atherosclerotic plaque formation but also the necrotic core formation was significantly enhanced. Lastly, we found a significant increase in p90RSK phosphorylation in the plaques from the IR-treated group compared to those from the non-IR treated group. Conclusions: Our results demonstrate that IR not only increases atherosclerotic events but also vulnerable plaque formation. These increases were a somewhat delayed effect of IR as they were observed in mice with PCL surgery performed 26 days, but not 10 days, after IR exposure. A proper animal model must be developed to study how to minimize the cardiovascular toxicity due to cancer treatment.

Radiation therapy (RT) in the form of photons and protons is a well-established treatment for cancer. More recently, heavy charged particles have been used to treat radioresistant and high-risk cancers. Radiation treatment is known to cause cardiovascular disease (CVD) which can occur acutely during treatment or years afterward in the form of accelerated atherosclerosis. Radiation-induced cardiovascular disease (RICVD) can be a limiting factor in treatment as well as a cause of morbidity and mortality in successfully treated patients. Inflammation plays a key role in both acute and chronic RICVD, but the underling pathophysiology is complex, involving DNA damage, reactive oxygen species, and chronic inflammation. While understanding of the molecular mechanisms of RICVD has increased, the growing number of patients receiving RT warrants further research to identify individuals at risk, plans for prevention, and targets for the treatment of RICVD. Research on RICVD is also relevant to the National Aeronautics and Space Administration (NASA) due to the prevalent space radiation environment encountered by astronauts. NASA’s current research on RICVD can both contribute to and benefit from concurrent work with cell and animal studies informing radiotoxicities resulting from cancer therapy. This review summarizes the types of radiation currently in clinical use, models of RICVD, current knowledge of the mechanisms by which they cause CVD, and how this knowledge might apply to those exposed to various types of radiation.

The details of valvular leaflet healing following valvuloplasty and leaflet perforation from endocarditis are poorly understood. In this study, the synthesis and turnover of valvular extracellular matrix due to healing of a critical sized wound was investigated. Twenty-nine sheep were randomized to either CTRL (n = 11) or HOLE (n = 18), in which a 2.8-4.8 mm diameter hole was punched in the posterior mitral leaflet. After 12 weeks, posterior leaflets were harvested and histologically stained to localize extracellular matrix components. Immunohistochemistry was also performed to assess matrix components and markers of matrix turnover. A semi-quantitative grading scale was used to quantify differences between HOLE and CTRL. After 12 weeks, the hole diameter was reduced by 71.3 ± 1.4 % (p

Objective. This review synthesizes the published literature on using mass media campaigns to reduce youth tobacco use, with particular focus on effects within population subgroups and the relative effectiveness of campaign characteristics. Data Source. A search of PubMed and PsycINFO conducted in March of 2014 yielded 397 studies with 34 suitable for inclusion. Study Inclusion and Exclusion Criteria. Included were quantitative studies that evaluate an antitobacco media campaign intended to influence youth cognitions or behavior or explore the relative effectiveness of campaign characteristics among youth. Data Extraction. An automated search and assessment of suitability for inclusion was done. Data Synthesis. Study outcomes were compared and synthesized. Results. Antitobacco media campaigns can be effective across racial/ethnic populations, although the size of the campaign effect may differ by race/ethnicity. Evidence is insufficient to determine whether campaign outcomes differ by socioeconomic status (SES) and population density. Youth are more likely to recall and think about advertising that includes personal testimonials; a surprising narrative; and intense images, sound, and editing. Evidence in support of using a health consequences message theme is mixed; an industry manipulation theme may be effective in combination with a health consequences message. Research is insufficient to determine whether advertising with a secondhand smoke or social norms theme influences youth tobacco use. Conclusion. Our recommendation is to develop antitobacco campaigns designed to reach all at-risk youth, which can be effective across racial/ethnic populations. Research priorities include assessing campaign influence among lower SES and rural youth, disentangling the effects of message characteristics, and assessing the degree to which this body of evidence may have changed as a result of changes in youth culture and communication technology.

Background Aortic regurgitation is a prevalent, detrimental complication of left ventricular assist devices (LVADs). The altered hemodynamics of LVADs results in aortic valves (AVs) having distinct mechanical stimulation. Our hypothesis was that the altered AV hemodynamics modulates the valve cells and matrix, resulting in changes in valvular mechanical properties that then can lead to regurgitation. Methods AVs were collected from 16 LVAD and 6 non-LVAD patients at time of heart transplant. Standard demographic and preoperative data were collected and comparisons between the two groups were calculated using standard statistical methods. Samples were analyzed using biaxial mechanical tensile testing, mass spectrometry-based proteomics, and transmission electron microscopy to assess ultrastructure. Results The maximum circumferential leaflet strain in LVAD patients was less than in non-LVAD patients (0.35 ± 0.10MPa versus 0.52 ± 0.18 MPa, p = 0.03) with a trend of reduced radial strain ( p = 0.06) and a tendency for the radial strain to decrease with increasing LVAD duration ( p = 0.063). Numerous proteins associated with actin and myosin, immune signaling and oxidative stress, and transforming growth factor β were increased in LVAD patients. Ultrastructural analysis showed a trend of increased fiber diameter in LVAD patients (46.2 ± 7.2 nm versus 45.1 ± 6.9 nm, p = 0.10), but no difference in fiber density. Conclusions AVs in LVAD patients showed decreased compliance and increased expression of numerous proteins related to valve activation and injury compared to non-LVAD patients. Further knowledge of AV changes leading to regurgitation in LVAD patients and the pathways by which they occur may provide an opportunity for interventions to prevent and/or reverse this detrimental complication.

Twitter is an online microblogging tool that disseminates more than 400 million messages per day, including vast amounts of health information. Twitter represents an important data source for the cancer prevention and control community. This paper introduces investigators in cancer research to the logistics of Twitter analysis. It explores methodological challenges in extracting and analyzing Twitter data, including characteristics and representativeness of data; data sources, access, and cost; sampling approaches; data management and cleaning; standardizing metrics; and analysis. We briefly describe the key issues and provide examples from the literature and our studies using Twitter data to understand public health issues. For investigators considering Twitter-based cancer research, we recommend assessing whether research questions can be answered appropriately using Twitter, choosing search terms carefully to optimize precision and recall, using respected vendors that can provide access to the full Twitter data stream if possible, standardizing metrics to account for growth in the Twitter population over time, considering crowdsourcing for analysis of Twitter content, and documenting and publishing all methodological decisions to further the evidence base.

Background Although extracellular xenograft repair has produced encouraging results when applied to cardiac, valvular, and specific aortic defects, its employment as a tube graft to replace the ascending aorta has not been reported. We describe a patient who underwent resection and replacement of an infected ascending aortic graft with an extracellular matrix conduit. The patient did well, but 14 months later developed a pseudoaneurysm from the staple line used to construct the extracellular matrix conduit. Methods The patient underwent a repeat sternotomy and removal of the graft. Because of the increased risk of graft failure, a homograft was felt to be more appropriate in this setting. Ultimately, we were unable to implant the homograft because it was too small for the aortic root; therefore we decided to construct a tubular graft from Cormatrix extracellular matrix (CorMatrix, Roswell, GA, USA). Fourteen months later, he presented with shortness of breath. Computed tomography scan revealed a 3.5 cm pseudoaneurysm of the ascending aorta. It appeared as if there was a disruption of the staple line in the extra cellular matrix graft. The plan was to replace it with a Dacron graft. Results The Cormatrix graft material was removed and sent for culture and histological analysis. A 28-mm Gel weave graft (Terumo Cardiovascular Systems, Ann Arbor, MI, USA) was implanted. The patient tolerated the procedure well with good hemodynamics. Conclusions Our experience suggests that the superior strength, handling characteristics, and resistance to infection make extra cellular matrix scaffold a possible alternative conduit to cryopreserved homografts. Applicability as an aortic conduit merits further investigation to better understand behavior of extra cellular matrix in this situation. doi: 10.1111/jocs.12583 (J Card Surg 2015;30:648–650)

During the course of both canine and human aging, the mitral valve remodels in generally predictable ways. The connection between these aging changes and the morbidity and mortality that accompany pathologic conditions has not been made clear. By exploring work that has investigated the specific valvular changes in both age and disease, with respect to the cells and the extracellular matrix found within the mitral valve, heretofore unexplored connections between age and myxomatous valve disease can be found. This review addresses several studies that have been conducted to explore such age and disease related changes in extracellular matrix, valvular endothelial and interstitial cells, and valve innervation, and also reviews attempts to correlate aging and myxomatous disease. Such connections can highlight avenues for future research and help provide insight as to when an individual diverts from an aging pattern into a diseased pathway. Recognizing these patterns and opportunities could result in earlier intervention and the hope of reduced morbidity and mortality for patients.

Calcific aortic valve disease (CAVD) encompasses the range of disease from initial alterations in the cell biology of the leaflets to end-stage calcification resulting in left ventricular outflow obstruction. The first detectable macroscopic changes in the leaflets, seen as calcification, or focal leaflet thickening with normal valve function, is termed aortic valve sclerosis, but it is likely that the initiating events in the disease process occur much earlier. Disease progression is characterized by a process of thickening of the valve leaflets and the formation of calcium nodules—often including the formation of actual bone—and new blood vessels, which are concentrated near the aortic surface. End-stage disease, eg, calcific aortic stenosis, is characterized pathologically by large nodular calcific masses within the aortic cusps that protrude along the aortic surface into the sinuses of Valsalva, interfering with opening of the cusps. There is no disease along the ventricular surface. For decades, this disease was thought to be a passive process in which the valve degenerates with age in association with calcium accumulation. Moreover, although CAVD is more common with age, it is not an inevitable consequence of aging. Instead, CAVD appears to be an actively regulated disease process that cannot be characterized exclusively as senile or degenerative. The National Heart, Lung, and Blood Institute convened a group of scientists from different fields of study, including cardiac imaging, molecular biology, cardiovascular pathology, epidemiology, cell biology, endocrinology, bioengineering, and clinical outcomes, to review the scientific studies from the past decade in the field of CAVD. The purpose was to develop a consensus statement on the current state of translational research related to CAVD. Herein, we summarize recent scientific studies and define future directions for research to diagnose, treat, and potentially prevent this complex disease process. ### Key Structure-Function Correlations Heart valves permit unobstructed, unidirectional forward flow through the circulation. …

Congenital cardiac valve disease is common, affecting ∼1% of the population, with substantial morbidity and mortality, but suboptimal treatment options. Characterization of the specific matrix and valve cell phenotypic abnormalities in these valves could lend insight into disease pathogenesis and potentially pave the way for novel therapies.Thirty-five human aortic and pulmonic valves were categorized based on gross and microscopic assessment into control valves (n=21); dysplastic valves, all except one also displaying hemodynamic changes (HEMO/DYSP, n=6); and hemodynamically altered valves (HEMO, n=8). Immunohistochemistry was performed on valve sections and flow cytometry on valvular interstitial cells.While both hemodynamically altered aortic and pulmonic valves demonstrated increased collagen turnover and cell activation, prolyl 4-hydroxylase and hyaluronan increased in hemodynamically altered aortic valves but decreased in hemodynamically altered pulmonic valves relative to control valves (P.001). HEMO/DYSP aortic valves demonstrated decreased collagen and elastic fiber synthesis and turnover compared to both hemodynamically altered aortic valves and control aortic valves (each P.006). Valvular interstitial cells from both hemodynamically altered and HEMO/DYSP pulmonic valves showed altered cell phenotype compared to control valves (each P.032), especially increased non-muscle myosin. Furthermore, valvular interstitial cells from hemodynamically altered pulmonic valves and HEMO/DYSP aortic and pulmonic valves each demonstrated greater size and complexity compared to control valves (each P.05).Dysplastic semilunar valves displayed alterations in collagen and elastic fiber turnover that were distinct from valves similarly exposed to altered hemodynamics as well as to control valves. These results demonstrate that dysplastic valves are not simply valves with gross changes or loss of leaflet layers, but contain complex matrix and cell phenotype changes that, with future study, could potentially be targets for novel nonsurgical treatments.

Aim Previous studies have reported that smokers who are misinformed about the safety of Nicotine Replacement Therapy (NRT) are less likely to report using it. In this study, we examined whether providing information that counters these concerns might impact on intentions to use NRT. Participants 900 smokers recruited from a market research database. Design and setting Participants completed an online survey that asked about their views about NRT. Smokers with safety and efficacy concerns were queried to determine whether accurate information might increase their interest in using NRT. Findings Misperceptions of NRT safety were common: 93% of smokers did not know that smoking while wearing the nicotine patch does not cause heart attacks; 76% that nicotine gum/lozenge are not as addictive as cigarettes; and 69% that NRT products are not as dangerous as cigarettes. Over half of the smokers with misperceptions reported that they would be more likely to use NRT to help them quit smoking if they were exposed to information correcting their concerns (53%, 58% and 66%, respectively, for each of the misperceptions). Conclusions These data suggest that while a sizeable proportion of smokers are still misinformed about the safety of NRT, misinformed smokers would increase consideration of NRT if these misperceptions are addressed by corrective information.

At birth, the mechanical environment of valves changes radically as fetal shunts close and pulmonary and systemic vascular resistances change. Given that valves are reported to be mechanosensitive, we investigated remodeling induced by perinatal changes by examining compositional and structural differences of aortic and mitral valves (AVs, MVs) between 2-day-old and 3rd fetal trimester porcine valves using immunohistochemistry and Movat pentachrome staining. Aortic valve composition changed more with birth than the MV, consistent with a greater change in AV hemodynamics. At 2 days, AV demonstrated a trend of greater versican and elastin ( P = 0.055), as well as greater hyaluronan turnover (hyaluronan receptor for endocytosis, P = 0.049) compared with the 3rd-trimester samples. The AVs also demonstrated decreases in proteins related to collagen synthesis and fibrillogenesis with birth, including procollagen I, prolyl 4-hydroxylase, biglycan (all P ≤ 0.005), and decorin ( P = 0.059, trend). Both AVs and MVs demonstrated greater delineation between the leaflet layers in 2-day-old compared with 3rd-trimester samples, and AVs demonstrated greater saffron-staining collagen intensity, suggesting more mature collagen in 2-day-old compared with 3rd-trimester samples (each P < 0.05). The proportion of saffron-staining collagen also increased in AV with birth ( P < 0.05). The compositional and structural changes that occur with birth, as noted in this study, likely are important to proper neonatal valve function. Furthermore, normal perinatal changes in hemodynamics often do not occur in congenital valve disease; the corresponding perinatal matrix maturation may also be lacking and could contribute to poor function of congenitally malformed valves.

The physiological mechanical environment of the intact mitral valve is presumed to allow mechanotransductive, cell–cell and cell-extracellular matrix (ECM) signaling, which regulates cellular remodeling of the tissue ECM composition and structure. The goal of this work was to design an organ culture system to mimic the mechanical aspects of this environment, which in the future should allow for investigations to probe mitral valve biology and remodeling. This flow loop organ culture system uses an electronically pressure-controlled bladder pump to create a range of physiological pressure pulses in a ventricular chamber gated by inflow and outflow valves. The mitral valve attachment within the system is designed to maintain proper anatomical geometry and function. The entire system is filled with a culture medium and located within an environmental incubator to provide an appropriate environment for tissue viability. The system has been shown to accurately recreate a physiologic pressure waveform (up to 150 mmHg) and induce pulsatile flow (3 L/min), with a response time of 50 ms. In addition, the system can maintain sterility and has been used to culture mitral valves for up to 3 weeks. This system approximately recreates the physiological mechanical environment of a mitral valve. Future experiments will validate its ability to maintain the normal structure and composition of porcine mitral valves. After validation, this organ culture system can be used in longer term studies of heart valve responses to stimuli such as various biochemical agents or altered hemodynamics.

Background Mass media campaigns can be an effective strategy to increase quitting activity among smokers, particularly when aired in the context of other anti-tobacco efforts. Design A longitudinal study using data collected from smokers identified in a random-digit-dial survey of adults in Grand Rapids MI, prior to the campaign and approximately 6 months after the launch of the campaign. Setting/participants Adult smokers who were interviewed in the fall of 2006 and agreed to participate in a follow-up interview approximately 6 months later ( n =212). Intervention A pilot mass media campaign, branded EX ® , which used empathy to encourage smokers to "relearn" life without cigarettes, and focused on disassociating smoking from common activities that would otherwise function as smoking cues, such as driving or drinking coffee. The campaign averaged 100 targeted rating points per week on television. Main outcome measures Primary outcome measures were five campaign-related cognitions and confidence in quitting. Secondary outcome measures were quitting behaviors. Results This 2007 analysis suggests that the campaign generated a high level of awareness of EX, with 62% of the sample demonstrating confirmed awareness and 79% reporting aided awareness. Awareness of EX was associated with significant change in two of five campaign-related cognitions. Awareness was not associated with confidence in quitting or having made a quit attempt. Conclusions These findings demonstrate that a branded, empathetic media campaign that offers smokers practical advice on how to approach quitting can change cognitions related to successful cessation over a relatively short time period.

Objectives. We examined the effectiveness of a program to increase exposure to national “truth” tobacco countermarketing messages among youths in rural and low-population-density communities. Methods. A longitudinal survey of 2618 youths aged 12 to 17 years was conducted over 5 months in 8 media markets receiving supplemental advertising and 8 comparison markets receiving less than the national average of “truth” messages. Results. Confirmed awareness of “truth” increased from 40% to 71% among youths in treatment markets while remaining stable in comparison markets. Over 35% of all youths who were unaware of the campaign at baseline became aware of it as a direct result of the increased advertising. Youths living in rural and low-population-density communities were receptive to the campaign's messages. Conclusions. Through purchase of airtime in local broadcast media, the reach of a national tobacco countermarketing campaign was expanded among youths living in rural and low-population-density areas. This strategy of augmenting delivery of nationally broadcast antitobacco ads can serve as a model for leveraging limited tobacco control resources to increase the impact of evidence-based tobacco prevention campaigns.

This article focuses on the development, implementation, and evaluation of a branded smoking cessation campaign piloted in four cities in the United States. The development of the EX brand and messaging strategies were based on existing public health literature and extensive formative research. Market segmentation was specifically employed to create messages that would resonate with a defined target audience, smokers who were thinking about quitting smoking. This approach led to the creation of a campaign with an empathetic and hopeful tone that was designed to change relevant beliefs about smoking and to increase smokers' self-efficacy in regard to quitting smoking. As part of a comprehensive evaluation, telephone surveys were conducted in three pilot cities to measure awareness of and receptivity to the EX brand. Awareness of EX varied across the three markets based on the media buy. Receptivity to the EX brand was high across the three samples comprised of three different racial/ethnic populations. High receptivity was also found among the target audience: smokers who were thinking about quitting smoking. Findings from this pilot campaign helped to inform the launch of a national smoking cessation campaign.

Aims To investigate the relation between aortic elastic properties and size in bicuspid aortic valves (BAVs). Methods and results 127 BAV outpatients (121 males; age 23 ± 10 years) with no or mild valvular impairment, were recruited with 114 control subjects comparable for age, gender, and body size. Aortic distensibility (DIS) and stiffness index (SI) were derived by M-mode evaluation of the aortic root together with blood pressure measured by cuff sphygmomanometer. BAVs vs. controls had increased aortic diameter ( P < 0.0001), higher systolic ( P = 0.02) and pulse ( P = 0.04) pressures. DIS was lower in BAVs than in controls (4.71 ± 3.67 vs. 7.44 ± 3.94 10−6 cm2dyne−1, respectively; P < 0.0001) and SI was greater in BAVs (7.21 ± 4.93 vs. 3.57 ± 1.88, respectively; P < 0.0001). Definite impairment in aortic elasticity was present in 53 (42%) BAVs. Both DIS and SI were related ( P < 0.0001) to aortic size in BAVs and controls. After adjusting for aortic size and blood pressure, the regression relations between SI and aortic diameter of BAVs were significantly different from controls ( P = 0.0052). Conclusion Abnormal aortic elasticity is a common finding in BAVs with no or mild aortic valve impairment. However, impaired aortic stiffness is not due to aortic dilation. Simple assessment of aortic size may thus fail to identify early abnormal load bearing characteristics of the aortic wall in BAVs.

Background— 3D stereolithographic printing can be used to convert high-resolution computed tomography images into life-size physical models. We sought to apply 3D printing technologies to develop patient-specific models of the anatomic and functional characteristics of severe aortic valve stenosis. Methods and Results— Eight patient-specific models of severe aortic stenosis (6 tricuspid and 2 bicuspid) were created using dual-material fused 3D printing. Tissue types were identified and segmented from clinical computed tomography image data. A rigid material was used for printing calcific regions, and a rubber-like material was used for soft tissue structures of the outflow tract, aortic root, and noncalcified valve cusps. Each model was evaluated for its geometric valve orifice area, echocardiographic image quality, and aortic stenosis severity by Doppler and Gorlin methods under 7 different in vitro stroke volume conditions. Fused multimaterial 3D printed models replicated the focal calcific structures of aortic stenosis. Doppler-derived measures of peak and mean transvalvular gradient correlated well with reference standard pressure catheters across a range of flow conditions ( r =0.988 and r =0.978 respectively, P r =0.985, P P =0.002). Conclusions— By combing the technologies of high-spatial resolution computed tomography, computer-aided design software, and fused dual-material 3D printing, we demonstrate that patient-specific models can replicate both the anatomic and functional properties of severe degenerative aortic valve stenosis.

© 2015, Biomedical Engineering Society. In this final portion of an extensive review of heart valve engineering, we focus on the computational methods and experimental studies related to heart valves. The discussion begins with a thorough review of computational modeling and the governing equations of fluid and structural interaction. We then move onto multiscale and disease specific modeling. Finally, advanced methods related to in vitro testing of the heart valves are reviewed. This section of the review series is intended to illustrate application of computational methods and experimental studies and their interrelation for studying heart valves.

Mitral valve regurgitation is a challenging clinical condition that is frequent, highly varied, and poorly understood. While the causes of mitral regurgitation are multifactorial, how the hemodynamics of regurgitation impact valve tissue remodeling is an understudied phenomenon. We employed a pseudo-physiological flow loop capable of long-term organ culture to investigate the early progression of remodeling in living mitral valves placed in conditions resembling mitral valve prolapse (MVP) and functional mitral regurgitation (FMR). Valve geometry was altered to mimic the hemodynamics of controls (no changes from native geometry), MVP (5 mm displacement of papillary muscles towards the annulus), and FMR (5 mm apical, 5 mm lateral papillary muscle displacement, 65% larger annular area). Flow measurements ensured moderate regurgitant fraction for regurgitation groups. After 1-week culture, valve tissues underwent mechanical and compositional analysis. MVP conditioned tissues were less stiff, weaker, and had elevated collagen III and glycosaminoglycans. FMR conditioned tissues were stiffer, more brittle, less extensible, and had more collagen synthesis, remodeling, and crosslinking related enzymes and proteoglycans, including decorin, matrix metalloproteinase-1, and lysyl oxidase. These models replicate clinical findings of MVP (myxomatous remodeling) and FMR (fibrotic remodeling), indicating that valve cells remodel extracellular matrix in response to altered mechanical homeostasis resulting from disease hemodynamics.

© 2014, Biomedical Engineering Society. In this portion of an extensive review of heart valve engineering, we focus on the current and emerging technologies and techniques to repair or replace the mitral valve. We begin with a discussion of the currently available mechanical and bioprosthetic mitral valves followed by the rationale and limitations of current surgical mitral annuloplasty methods; a discussion of the technique of neo-chordae fabrication and implantation; a review the procedures and clinical results for catheter-based mitral leaflet repair; a highlight of the motivation for and limitations of catheter-based annular reduction therapies; and introduce the early generation devices for catheter-based mitral valve replacement.

© 2014, Biomedical Engineering Society. The engineering of technologies for heart valve replacement (i.e., heart valve engineering) is an exciting and evolving field. Since the first valve replacement, technology has progressed by leaps and bounds. Innovations emerge frequently and supply patients and physicians with new, increasingly efficacious and less invasive treatment options. As much as any other field in medicine the treatment of heart valve disease has experienced a renaissance in the last 10 years. Here we review the currently available technologies and future options in the surgical and transcatheter treatment of aortic valve disease. Different valves from major manufacturers are described in details with their applications.

In 2014, the Food and Drug Administration (FDA) launched its first tobacco-focused public education campaign, The Real Cost, aimed at reducing tobacco use among 12- to 17-year-olds in the United States. This study describes The Real Cost message strategy, implementation, and initial evaluation findings. The campaign was designed to encourage youth who had never smoked but are susceptible to trying cigarettes (susceptible nonsmokers) and youth who have previously experimented with smoking (experimenters) to reassess what they know about the "costs" of tobacco use to their body and mind. The Real Cost aired on national television, online, radio, and other media channels, resulting in high awareness levels. Overall, 89.0% of U.S. youth were aware of at least one advertisement 6 to 8 months after campaign launch, and high levels of awareness were attained within the campaign's two targeted audiences: susceptible nonsmokers (90.5%) and experimenters (94.6%). Most youth consider The Real Cost advertising to be effective, based on assessments of ad perceived effectiveness (mean = 4.0 on a scale from 1.0 to 5.0). High levels of awareness and positive ad reactions are requisite proximal indicators of health behavioral change. Additional research is being conducted to assess whether potential shifts in population-level cognitions and/or behaviors are attributable to this campaign. Current findings demonstrate that The Real Cost has attained high levels of ad awareness which is a critical first step in achieving positive changes in tobacco-related attitudes and behaviors. These data can also be used to inform ongoing message and media strategies for The Real Cost and other U.S. youth tobacco prevention campaigns.

Tobacco companies have recently introduced products that they claim have reduced toxins and carcinogens, and that they say may be less harmful to smokers. These are potential reduced exposure products, or PREPs. This study measured smokers' awareness of PREPs, use of PREPs, interest in trying PREPs, and beliefs about the regulation of PREPs. This study was based on nationally representative data collected in 2002 and 2003 through the American Smoking and Health Survey. The final sample included 1,174 adult smokers. Descriptive and multivariate analyses were conducted to produce estimates and explore potential correlates of the outcomes. A total of 41.9% of adult smokers reported having heard of at least one of the PREPs measured, and 11.0% reported having tried one of these products. Half of adult smokers (49.9%) said they would like to try PREPs. Interest in trying PREPs was associated with having made a quit attempt, being concerned about the effect of smoking on one's health, and having a household income of less than US dollars 20,000. About half of adult smokers (49.1%) incorrectly believed that PREPs are evaluated for safety by the government before being placed on the market, and 84.2% believed that the government should evaluate the safety of PREPs before they are sold to consumers. This study provides new and timely information on the use of, interest in trying, and beliefs about the regulation of PREPs among a nationally representative sample of adult smokers. With half of adult smokers interested in trying PREPs, the need for concrete scientific evidence on the potential impact of these products is critical.