Denis B. Buxton

Recommendations of the National Heart, Lung, and Blood Institute Nanotechnology Working Group

Recent rapid advances in nanotechnology and nanoscience offer a wealth of new opportunities for diagnosis and therapy of cardiovascular, pulmonary, and hematologic diseases and sleep disorders. To review the challenges and opportunities offered by these nascent fields, the National Heart, Lung, and Blood Institute convened a Working Group on Nanotechnology. Working Group participants discussed the various aspects of nanotechnology and its applications to heart, lung, blood, and sleep (HLBS) diseases. This report summarizes their discussions according to scientific opportunities, perceived needs and barriers, specific disease examples, and recommendations on facilitating research in the field. An overarching recommendation of the Working Group was to focus on translational applications of nanotechnology to solve clinical problems. The Working Group recommended the creation of multidisciplinary research centers capable of developing applications of nanotechnology and nanoscience to HLBS research and medicine. Centers would also disseminate technology, materials, and resources and train new investigators. Individual investigators outside these centers should be encouraged to conduct research on the application of nanotechnology to biological and clinical problems. Pilot programs and developmental research are needed to attract new investigators and to stimulate creative, high-impact research. Finally, encouragement of small businesses to develop nanotechnology-based approaches to clinical problems was considered important.

Nanomedicine for the management of lung and blood diseases.

Nanotechnology provides a broad range of opportunities to develop new solutions for clinical problems. For the pulmonary field, nanotechnology promises better delivery of drugs and nucleic acid-based therapeutics to disease sites. Administration of therapeutics via inhalation provides the opportunity for direct delivery to the lung epithelium, the lining of the respiratory tract. By appropriate selection of particle size, deep lung delivery can be obtained with control of phagocytic uptake, the removal of particles by resident macrophages. Nanotechnology can also help in pulmonary therapies administered by intravenous and oral routes through targeting specific cell types and controlling bioavailability and release kinetics. In the hematology field, nanotechnology can counter multiple drug resistance in leukemia by blocking drug efflux from cancer cells, and provide effective delivery of siRNA into lymphocytes to block apoptosis in sepsis. Controlling the surface properties of materials on devices such as valves and stents promises improved biocompatibility by inhibition of thrombosis, the formation of blood clots, and regulating cell adhesion and activation. Nanoparticle-based thrombolytic agents have the potential to improve the effectiveness of clot removal. Treatment of both lung and blood diseases is also likely to benefit from nano-scaffold-based methods for controlling the differentiation and proliferation of stem and progenitor cells.

Report of the National Heart, Lung, and Blood Institute Working Group on the Translation of Cardiovascular Molecular Imaging

Imaging has become an indispensable tool in cardiovascular research, clinical trials, and medical practice. Traditional imaging modalities provide primarily anatomic as well as some physiological information. The emerging field of molecular imaging aims to expand beyond these traditional targets to visualize specific biochemical structures or biological processes. Platforms under exploration for molecular imaging include ultrasound, single-photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), and optical techniques, such as fluorescence-mediated tomography (FMT) and catheter-based sensors. Ultimately, molecular imaging may allow clinicians to reach beyond anatomy to visualize the expression and activity of particular molecules, cells, or functions that influence disease progression, outcome, and/or responsiveness to therapeutics. The last 3 decades have seen explosive growth in the application of cardiovascular molecular imaging, as demonstrated by a recent PubMed search (Figure). Despite basic science advances, translation into clinically available agents and techniques has lagged. In September 2009 the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of experts in the fields of molecular imaging and cardiovascular disease to assess the current state of molecular imaging and its application to cardiovascular diseases, to identify areas where cardiovascular molecular imaging was likely to have an impact, to explore barriers to the translation of molecular imaging toward clinical application, and to inform the NHLBI on national priorities for the promotion of translation of cardiovascular molecular imaging. Here, we summarize state-of-the-art technologies, their challenges, clinical needs, and specific recommendations of the working group. Figure. Cardiovascular molecular imaging publications from 1987 to 2010. The Scopus database was searched for the terms “molecular” and “imaging” in the title or abstract, and the results obtained were then restricted further by searching on “cardiovascular.” The results obtained from the restricted search were then checked manually to include only original research articles …

American society of echocardiography cardiovascular technology and research summit: A roadmap for 2020

From the Divis (P.A.P., M.E.S Medicine, Dur Washington U Baltimore, M Germany (R. Maryland (D. Tennessee (B Hackensack U Healthcare, H Mountain View Oregon Healt Clinic, Clevel Chicago, Illino Ontario, Can Bioengineerin Menlo Park, DeBakey Hea (M.L.M., S.F University o Institute/Lava General Hosp M.S.-C.); the Philips Healt Irvine, Califor (G.S.S.); Yale Imaging, Nor San Francis Pennsylvania Center, Wash

Calcium-dependent Threonine Phosphorylation of Nonmuscle Myosin in Stimulated RBL-2H3 Mast Cells

Stimulation of RBL-2H3 m1 mast cells through the IgE receptor with antigen, or through a G protein-coupled receptor with carbachol, leads to the rapid appearance of phosphothreonine in nonmuscle myosin heavy chain II-A (NMHC-IIA). We demonstrate that this results from phosphorylation of Thr-1940 by calcium/calmodulin-dependent protein kinase II (CaM kinase II), activated by increased intracellular calcium. The phosphorylation site in rodent NMHC-IIA was localized to the carboxyl terminus of NMHC-IIA distal to the coiled-coil region, and identified as Thr-1940 by site-directed mutagenesis. A fusion protein containing the NMHC-IIA carboxyl terminus was phosphorylated by CaM kinase II in vitro, while mutation of Thr-1940 to Ala eliminated phosphorylation. In contrast to rodents, in humans Thr-1940 is replaced by Ala, and human NMHC-IIA fusion protein was not phosphorylated by CaM kinase II unless Ala-1940 was mutated to Thr. Similarly, co-transfected Ala → Thr-1940 human NMHC-IIA was phosphorylated by activated CaM kinase II in HeLa cells, while wild type was not. In RBL-2H3 m1 cells, inhibition of CaM kinase II decreased Thr-1940 phosphorylation, and inhibited release of the secretory granule marker hexosaminidase in response to carbachol but not to antigen. These data indicate a role for CaM kinase stimulation and resultant threonine phosphorylation of NMHC-IIA in RBL-2H3 m1 cell activation.

Molecular Imaging of Aortic Aneurysms

Aortic aneurysms (AAs) are life-threatening permanent dilations of the aorta, frequently defined by a diameter of 1.5 times normal.1 They are subdivided anatomically into thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs). The underlying pathogenesis differs between the 2 anatomic sites; for TAAs, the histological abnormality is medial degeneration characterized by loss of smooth muscle cells, fragmented and diminished elastic fibers, and accumulation of proteoglycans.2,3 Genetic mutations are the underlying cause of TAAs in many young or middle-aged patients.4 In contrast, the histopathology of AAAs is dominated by severe intimal atherosclerosis, chronic transmural inflammation, and remodeling of the elastic media.2,3 Analysis of gene expression demonstrated that AAAs and TAAs exhibit distinct patterns with most changes relative to normal aortas unique to each disease.3 However, several risk factors are shared between TAAs and AAAs, including smoking, hypertension, male sex, and aging.2 The age and sex dependence is illustrated by the prevalence of AAAs 2.9 to 4.9 cm in diameter, ranging from 1.3% in men aged 45 years to 54% to 12.5% at ages 75 to 84 years. For women the prevalence for the same age groups is 0% and 5.2%, respectively.5 The prevalence of TAAs also increases with age and is higher in men.6 If untreated, AAs can expand and eventually rupture, resulting in death rates as high as 90%; in 2009, mortality in the United States from AAs and dissections was >10 500.7 Both expansion rates and rupture rates of AAs increase with aneurysm size. Diagnosis of AAs generally involves anatomic imaging, typically ultrasound or CT angiography, and once diagnosed, risk stratification involves measurement of diameter by CT angiography.8 There has been controversy concerning the value of population screening for AAAs, but the Multicenter Aneurysm …

A Summary of the American Society of Echocardiography Foundation Value-Based Healthcare: Summit 2014 : The Role of Cardiovascular Ultrasound in the New Paradigm

Value-Based Healthcare: Summit 2014 clearly achieved the three goals set forth at the beginning of this document. First, the live event informed and educated attendees through a discussion of the evolving value-based healthcare environment, including a collaborative effort to define the important role of cardiovascular ultrasound in that environment. Second, publication of these Summit proceedings in the Journal of the American Society of Echocardiography will inform a wider audience of the important insights gathered. Third, moving forward, the ASE will continue to build a ‘‘living resource’’ on its website, http://www.asecho.org, for clinicians, researchers, and administrators to use in advocating for the value of cardiovascular ultrasound in the new value-based healthcare environment. The ASE looks forward to incorporating many of the Summit recommendations as it works with its members, legislators, payers, hospital administrators, and researchers to demonstrate and increase the value of cardiovascular ultrasound. All Summit attendees shared in the infectious enthusiasm generated by this proactive approach to ensuring cardiovascular ultrasound’s place as ‘‘The Value Choice’’ in cardiac imaging.

The impact of nanotechnology on myocardial infarction treatment.

173 ISSN 1743-5889 10.2217/NNM.11.184 Nanomedicine (2012) 7(2), 173–175 “Nanotechnology has the potential to play a role in improving outcomes from MI at multiple points in the disease process. These include earlier and more sensitive diagnosis of developing MI, improved treatments of acute MI with drugs, cell therapy and siRNA, and tissue engineering approaches for preventing infarct expansion and the development of heart failure.”

Support for Cardiovascular Cell Therapy Research at the National Heart, Lung, and Blood Institute

Heart failure (HF) exerts an enormous burden both in the United States and worldwide, compounded by the lack of effective therapies for patients with end-stage HF. Current options other than medical management are limited to cardiac transplantation, severely limited by the lack of donor availability, and ventricular assist device (VAD) implantation. Although the introduction of newer VADs has reduced complications such as thrombosis and infection, mortality in patients with VADs is still significant (≈25% in the first year1). Since the capacity of the heart to repair itself after myocardial infarction (MI) is very limited, effective regenerative therapies for patients with large acute MI to prevent progression to HF would be highly beneficial in decreasing the morbidity and mortality associated with end-stage HF. Regenerative therapies to repair failing hearts have the potential to provide new options for patients with advanced HF who currently face low quality of life as well as poor prognosis. ### National Heart, Lung, and Blood Institute Cardiovascular Cell Therapy Research Network Clinical trials to test the ability of cell therapy to treat patients after MI were initiated a decade ago in Europe with injection of autologous skeletal myoblasts in patients undergoing coronary artery bypass surgery,2 followed rapidly by trials using other cell types and delivery routes. In response to the proliferation of non-US cell therapy trials, the National Heart, Lung, and Blood Institute (NHLBI) held a working group in August 2004 to assess the status of clinical studies of cell-based therapies for cardiovascular disease, to determine the gaps in knowledge and barriers that prevent the implementation of well-designed and safe clinical studies. Another charge to the working group was to identify the areas of opportunity to apply cell-based therapies for cardiovascular disease.3 The primary recommendation of the working group was the formation of a cardiovascular cell therapy research network, consisting of a clinical research network component …

Nanotechnology Research Support at the National Heart, Lung, and Blood Institute

The field of nanotechnology is growing explosively and impinging on all walks of life. This is reflected in the appearance of nanotechnology in consumer products; in March 2011, the Project on Emerging Nanotechnologies, a partnership between the Woodrow Wilson International Center for Scholars and the Pew Charitable Trusts, reported more than 1300 consumer products containing nanotechnology on the market, a growth of 520% since March 2006.1 The health care field is also being affected; a search on “nanoparticle” in ClinicalTrials.gov pulls up more than 80 trials, primarily in the cancer field but also including such diverse areas as antibacterial agents, dental composites, wound dressings, imaging agents, and stent coatings. What does “nanotechnology” refer to? The National Nanotechnology Initiative defines nanotechnology as the understanding and control of matter at dimensions between approximately 1 and 100 nm, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale.” There are 2 approaches to nanotechnology, termed “top-down” and “bottom-up.” Top-down approaches involve the use of tools to make nanoscale features, for example, nanopatterning of surfaces on devices to change their surface properties. Bottom-up approaches involve self-assembly of small components to make nanoscale particles or structures. ### National Heart, Lung, and Blood Institute Programs of Excellence in Nanotechnology Early last decade, the National Heart, Lung, and Blood Institute (NHLBI) recognized the promise of nanotechnology for improving the diagnosis and treatment of heart, lung, and blood diseases, and in 2003 the institute organized a working group to give advice on how to harness this potential. The working group brought together physical scientists such as chemists and material scientists, along with biological scientists and clinicians from the heart, lung, and blood fields. The highest-priority recommendation of the working group was the formation of multidisciplinary centers that would promote collaborations between the biological and physical …