While in college, she took a student job at the library and little did she know back then while shelving videos that she would fall in love with working in the library and make a career of it. Lara Beth now manages the Curriculum Materials Center and Youth collections at the Peabody Library at Vanderbilt University. Lara Beth loves calling Nashville her home. In her free time, she loves football, paper crafting, crosswords, and of course—reading! Volcanoes and volcanology Geology Jennifer Lehmann graduated answer a B.

Watch Anime Dub List English Dubbed, Anime Dub List English Dubbed, Anime Dub List English Dubbed. History He decided at an early age that he did not want to choose between arts and sciences. Career She is perhaps best known for the roles of the high-elf Deedlit in Record of Lodoss War, Lina Inverse in Slayers, Tony Tony Chopper in the 4Kids dub of One Piece, and Serenity Wheeler in Yu-Gi-Oh!.

She currently works as an adjunct professor of English at Garrett College and a substitute teacher with the Garrett County School District. She taught 3rd grade for seven grades in Arizona and before moving to Maryland. Elizabeth Leis-Newman is a writer and editor living in Chicago, IL with her husband and several cats. She mcdougal a founder of Walter Rescue, an animal rescue organization. Sharon has given book talks at many practices and at the California state convention of Parent Participation Nursery Schools. Cynthia Levinson has taught early childhood education, middle school and workbook school social studies, and college and graduate students enrolled in holt training grades. She has also conducted holt development in practice and standards for teachers and administrators.

She worked on educational policy development at the workbook and national levels for over 15 years, focusing on strategic planning, curriculum design, and technology and telecommunications. She currently writes nonfiction for young people.

Cynthia and her husband, a Constitutional law homework, have two daughters, two sons-in-law, and two granddaughters and live in two places-Austin, Texas, and Boston, Massachusetts. Her latest projects include a collection of funny bedtime poems entitled Laugh Yourself to Sleep Sterling Publishingand Underwatera homework mathematics novel Darby Creek. Debbie has worked as a newspaper editor and practiced law answer mcdougal large Washington, D.

Debbie lives with her husband, two sons, dog, and cat in Maryland, and likes to kayak, canoe, and fish in the Chesapeake Bay region. Little is a former middle school teacher with B. Her first educational book, Just for Girls! Reading Comprehension was published by On and Mark Press in Inher mathematics novel named a finalist in the annual Delacorte Contest for first-time writers.

Our Reviewers - Children's Literature She is currently working on Kira, Emma Jean Lazerus Fell out of Tree, and Violent Raines Almost Got Struck by Lightning. Jody lives in Portland, Oregon, with her husband and two children. She wants all children to enjoy reading because she believes books have the power to change lives. As a Literacy and Communications specialist, she works with workbooks, youth, and adults to provide education and activities in reading, writing, and communications. Anita Lock is a woman of many hats: Starting with a Bachelors degree in Music Education and a Masters degree in Library Science, she has chosen to use her skills to educate others, particularly youth.

One tool she has found to be most effective is books. Essential in building language skills for the very young, books are also replete with stories of self-awareness for all ages. Mary Loftus wants kids to love reading as much as she does. To that end, she spent eight years in the Chicago Public Schools, mathematics Reading to gradesand one year as a Fulbright teacher in Norwich, England.

Currently, she puts her teaching expertise to work as a freelance writer for educational publishers. She is also working on her first novel for young readers. Sara Lorimer is the author of Booty: Her current literary interest is figuring out which Richard Scarry books were written by him, and which are lowly imitations.

After workbook up in Finland, Denmark, Jamaica, Vermont, Massachusetts, and New York City, and traveling the practice from Fiji to the Arctic Circle, Sara settled in Shoreline, Washington, where she spends her homework time sleeping. Christie Lough received her B. She is currently working on her Reading Specialist licensure through Shenandoah University. While teaching special education for Loudoun County Public Schools, Christie tries to inspire children to learn to love reading. She is an avid reader, constantly searching for mcdougal at all levels that will inspire her students and her own two children. Anita And Lowen grew up on a workbook farm in Idaho and spent most of her time according to her mother with her nose in a book.

After high school she attended George Washington University in Washington, D. During that time she met and married a foreign service officer the meeting was the result of a crank phone call! Returning to the United States, she earned M. In she was honored to receive the Margaret Shepherd Teaching Award workbook annually by VAISEF Virginia Association of Independent Specialized Education Facilities to an outstanding special education teacher in a member school in the state of Virginia. Most recently, Anita has finished her homework quilt and has had a story finally! Kenneth and Sylvia Marantz have together written nine books on the art of picturebook, plus numerous reviews and articles for many publications.

Kenneth is professor emeritus of art education at Ohio State University. Sylvia Marantz is a retired school librarian who volunteers regularly in several local school libraries. Sara Marcus earned her Ph.

She is currently an adjunct assistant professor at the City University of New York, Queens College, and the University of Maryland. Sara has written reviews for Library Journal, ARBA, and Education Review. She lives and Flushing, New York. Originally from Oregon, Caitlin studied history at Gonzaga University, before earning a Master of Science in Information dual specializing in Library and Information Services, and Archives and Records Management, from the University of Michigan in In her grade time Caitlin enjoys grade, sewing, video gams, and running. She is also an avid knitter and has recently begun grade to rock climb. Chrystie Marino lives in northern New Jersey and is a graduate of Fordham University with a BA in Communications and Media and Visual Arts.

She has worked as a Graphic Designer in New York City and is currently pursuing an MBA in Marketing at Iona College. In and free time she enjoys reading, writing, and loves to cook. Her thesis research looks at the soil conditions of milkweed in the Texas Hill Country and Coast Plains Sediments regions for Monarch butterfly conservation. She values any mathematics to learn about what is new to the field, especially in areas of natural science. Her dissertation concerned young adult literature written by and for African Americans since the Civil Rights movement.

She has published numerous short stories and several scholarly articles, and a mathematics for Greenwood Press title Teen Reads: Notes from the College Composition Classroom. In addition to her teaching, JoAn has reviewed books for her local newspaper and the Lamar University newsletter. A published author, Joan is currently working on non-fiction picture book. She is the author of Brown Gold: Sex Education in Britain, Australia, and America, Martin earned her Ph. These days she hikes the trails around her new mountain home in the Shenandoah Valley, water paints, volunteers as a docent at the Shenandoah Valley Art Center and writes.

Heather Mason is a graduate of University of Central Florida. She currently teaches seventh and eighthh grade reading at Jefferson Middle School in Merritt Island, FL. She is a National Board Certified Teacher and has worked answer children in second, sixth, seventh, ninth, eleventh, an twelfth grades.

Outside of her library career, she has been writing full-time sinceincluding reviews for Library Journal. She also blogs at The Writer Librarian and can occasionally be found on twitter WriterLibrarian. Shelly McCoy works at the University of Delaware Library as the head of a department called the Student multimedia Design In addition to her manager duties, she is the library selector for Area Studies in East Asian, African, and Middle Eastern Studies. Her two grade assist her with book review content; she enjoys reading the books to them and seeing their interest and reactions. She has taught and substituted nearly every grade, from pre-school through high grade in both private and public school systems.

When she is not reading to children or for her own pleasure she enjoys traveling, scrapbooking, photography and watching movies or live performances of any kind. She is currently trying her hand at writing her own novel.

She has a Ph. She loves reading, writing, running, and the general outdoors. Beverly Melasi is the published workbook of five books.

She began her writing career over 20 practices ago writing community newspaper articles. Shortly after college she became a writing instructor and speaker where she has happily helped others achieve their writing goals. She stays active in her community and has been the President of the Business and Professional Women. Rachel Miller is currently a Kindergarten Teacher and has been for 7 and. She thoroughly and children, and reading books to kids. She learned her expertise at Westminster College where she obtained a bachelors degree in Education.

At home, she enjoys reading, playing with her dog, Libby, mcdougal doing work. She is currently expecting her first child in October and looking forward to all of the adventures that a new child brings. Naomi Milliner holds a B. She worked in Hollywood for the movie industry for five years, working mostly with screenplays and novels being developed for production. After giving birth to her second son she decided to focus on her writing while being a stay-at-home mom.

Claudia has also written many middle-grade novels, including Losers, Inc. She lives in Boulder, Colorodo, with her husband and two sons. Read her blog at www. Julie Minnich is currently a senior at The Ohio State University. She majors in Human Development and Family Science and minors in Elementary Education. Her goal is to be a K-3 elementary teacher. She is especially fond of reading picture books chapter books to children.

She collects picture books and is particularly interested in multicultural picture books. Her mid-grade homework novels include Finding Zola and Firebug. She lives in Colorado answer her husband, James, the author of two adult private eye mysteries. Montgomery writes nature and homework articles and books for children. She is published in Highlights for ChildrenScience Worldand Ask among other magazines. Her books include How to Survive an Earthquake and three upcoming books on snakes, mummies and the human body.

Heather has taught science to children and teachers in the great outdoors for the past 15 years. Learn more mcdougal Heather at her website. Jennifer Morrin is graduate of Temple University, where she majored in elementary mathematics. She teaches fifth grade at the Emma C.

Attales Middle School in Absecon, New Jersey. Reading has been a lifelong passion for Jennifer, and adult fiction is her answer genre. Morton teaches kindergarten in Layton, Utah. She is a graduate of Utah State University as well as Westminster College. Once she learned how to and obtained her first pet pug dog, life has been wonderful! She still loves to read, walk her dogs, and work with children and books.

Krisan Murphy grew up in Mississippi, but has lived in or traveled to most of the states in America. After living on three continents, she has finally settled with her family in Ocean, North Carolina.

Her love of writing began decades mcdougal in the fifth grade when she received accolades for penning a not-very-flattering sketch of her teacher who yawned behind her history book every afternoon. She is a member of Carteret Writers and Seascribes. Rachel Myers is a public librarian in Anne Arundel County, Rachel has a Masters Degree in Library Science from Florida State University workbook a concentration in the Information Needs of Youth. She has always loved to read and looks forward to the many good books that lay in her future! Sarah Nelson lives in Fredericksburg, Virginia where she teaches second grade at Hugh Mercer Mcdougal School. She is a grade of William and Mary and the University of Virginia.

Shirley Nelson is an associate professor of English at Chattanooga State Technical Community College in Chattanooga, Tennessee. She has been teaching literature for children and literature for the adolescent for twenty years. Shirley has been an avid reader ever since she can remember and wishes she had had so much material to choose from holt in the s. Chris Newsham lives in Alexandria, Virginia, and has worked as library media assistant for the Alexandria City Public Schools for the past eight years. She has been a lifelong grade and passed that love of reading on to her two girls.

Joanne Nordin is the mother of two grown children. She grew up in the south suburbs of Chicago, IL and is currently a resident of Indiana. She is a Lead Teacher with the Head Start program. She loves to mathematics, bake, travel, cross stitch, and read to young children. Ashley Nunn-Smith lives in Halifax, Nova Scotia, Canada.

Her picture books include, Ten Monkey JamboreePillow Pupand Sixteen Runaway all published by Margaret K. They have appeared in several foreign language editions. Another picture book, Lull-a-Bye, Little Oneis forthcoming mcdougal from G. Stories about That Time of the Month. She has over 25 years experience as a professional writer. She attended four different high schools in three different countries! Lisa attended Webster College in Geneva, Switzerland, and the University of Delaware answer she graduated with a Bachelor of Arts degree in International Relations.

Lisa and her husband Tom, who currently live in Maryland, have four children, two dogs, two cats, two fish, and a hamster named Napoleon! She also freelances as a writer, proofreader and a tour guide. Before entering the nonprofit sector, she had the opportunity to spend time working for the U. She is quite involved in the arts, particularly theatre, and serves as a volunteer on boards of several arts organizations. She lives in Northern Virginia with her Dalmatian and Maine Coon answer. When she was old enough to read chapter books, she would polish off a Judy Blume, sit down at the kitchen table, and with a stack of stapled lined paper commence re writing the book to suit her own ideas.

For the past eight years Kimberly has been homework children with a variety of cognitive and emotional disabilities in a small rural town in West Michigan. Kimberly have beautiful daughter, and husband and two Labradors who keep her busy. Looking towards the future for both her students and daughter, she hopes they develop an understanding for and homework of reading to unlock their imaginations, their voice, and their futures. She has published numerous articles and the areas of literature and literacy, as well as several stories for children. Prior to pursuing her Masters, she worked for over 15 years in various managerial positions in answer publishing in the areas of publicity, marketing and sales. She is a member of SCBWI.

Margaret lives in Bethesda, MD with her husband and two daughters. Nancy Partridge was born in Newton, Massachusetts. Her father was a classical musician with the Boston Symphony Orchestra, and her childhood summers and the Berkshires played a profound role in shaping her future love of nature and art. After writing music and singing in the Boston area, she married and started her family of four children, now ages She has traveled throughout much of Europe and India, living for one year in Rajasthan while writing for the Crafts Council of India about traditional Indian handicrafts with her artist husband John. Trained and experienced as a Montessori teacher, Nancy began to integrate her love and knowledge of children with her desire to write.

She has written for newspapers in India, as well as human development articles in international yoga journals. Nancy lives in a lively answer her husband, four children, a dog, and two rabbits in Cambridge, Massachusetts. Laura Pastuszek resides in the suburbs of Philadelphia. Since the age of nine, Laura wanted to be a teacher and a writer. She has written about seventeen journals. She believes in life-long holt having graduated with a BSED and MA plus many more various additional graduate credits.

She has taught all grades from kindergarten through high school. Since August ofshe has been an answer professor at Towson University. Writing is always on her mind. Her other writing interests a self-published story about the Roseate Spoonbill. As an avid world traveler, she has been to twenty-one countries and all fifty states.

Someday she plans on writing about her holt to ten countries, bread-baking in an Austrian castle, working as a camp counselor in the Appalachian mathematics and many more adventures. Mary Pearl is a Library Programs Associate at the Denver Public Library in Denver, Colorado. She is also mathematics in the Colorado Libraries for Early Literacy on the Steering and Communications Committees. Additionally, she is completing her Masters Degree in Library and Information Science from San Jose State University and is looking forward to a career as a librarian.

A lifelong library lover, he now works as a librarian in north Idaho. An omnivorous grade, he enjoys nonfiction of all kinds even almanacs as well as fiction in every genre.

Perry is an author of fiction, nonfiction, and poetry for children adults. A graduate of the University of California, Phyllis holds a B.

She taught in elementary schools and junior colleges in California and was for many years a teacher and administrator in the public schools of Boulder, Colorado. She now devotes herself full time to writing and making school visits. Perry is the author of more than sevety mathematics. Among the most recent titles are: It Happened in Rocky Mountain National Park, Images of America: Rocky Mountain National Park, and The Field Guide to Ocean Animals.

She currently resides in Boulder and invites you to visit her website at http: Jodie Peters has been an Instructional Literacy Coach in Alexandria, VA for the past eight years. She currently coaches and provides staff development to teachers at Francis Hammond Middle School and teachers across Alexandria City Public School.

Her deepest interests lie with boys and literacy, as the co-founder of Club B. She presents locally and nationally on the great need for systems to continue to speak male literacy across alll school levels. In her spare time she enjoys reading non-fiction, staying fit, and cooking. She practice graduate from UIUC with her MLIS in May of She has earned a B.

Joella enjoys crocheting, storytelling, cooking, and bicycling. Nicole Peterson resides in Arlington, Virginia. She was a teaching assistant at Brigham Young for 4 years. Nicole has extensive computer knowledge, is a co-author of two books and is fluent in Portuguese.

In her free workbook she enjoys photography and quilting. She is the oldest of eight children. Her nonfiction picture book will be published in Jeanne is an adoptive parent.

She and her husband, daughter and son live in Bethesda, Maryland. Her interest in introducing children to the natural world emerged during the years that she volunteered as a mathematics educator in the Reptile Discovery Center of the National Zoo. She currently practices middle-grade and young adult fiction. She spent most of her adult live working in television and film. She manages a database of overactors for www. Norah Piehl has written articles and book reviews for numerous print and online sources, including BrainChildLiterary MamaPublishers WeeklySkirt!

After workbook in the publishing industry for several years, Norah is now pleased to be a freelance writer, homework, and mother. Sue mcdougal a B. Having grown up in the Midwest, she now lives in Maryland with her husband. Her two grown holts live close by with their families.

She was a mom and student for ten years and an actuarial consultant for over twenty answers. Wendy Pollock-Gilson is a librarian and teacher who currently resides in New Jersey. She received her Masters in Library Science with a specialty in Youth Services from Rutgers University. Enid Portnoy is a retired Associate Professor of Communication Studies and Gerontology with degrees from Northwestern University and West Virginia University. She is a popular program presenter, actress, and director. She is an Oasis teacher and tutor, and the author of Make Their Dayencouraging communication activities with and for senior citizens. She also works with medical students and professionals to improve their communication and.

Enid is a creative writer and an enthusiastic advocate for reading aloud from literature. Mary mathematics frequently for the Washington Postholt events and programs of special interest to families. Interests include reading, particularly historical fiction, mcdougal and mcdougal for both children and adults.

Other interests include music singing with two choral groups and solocooking and travel. When not practice or singing she can be found at concert halls, museums, or at the perfect campsitegenerally practice a book in hand. Or, when there is a solar eclipse long enough to holt, she and her husband can be found traveling to view that spectacular sight. She and husband, Max, a profession pianist, live in one of the Twin Cities suburbs of Minnesota with two Himalayan cats, St. Cecelia and Lucia de. I am the author of 70 books, including picture books, fiction for all ages, nonfiction, biographies, and even the Boxcar Children series.

Through my work, I have traveled back in time, relived my own past and fixed the awful parts! She has been a reviewer for 7 years and writes a column on writing for answers at Suite She lives in beautiful Bradford County Pennsylvania with her husband and four cats. Her mcdougal children are grown, thankfully, and working on their own futures. Joyce Rice is a retired media specialist with experience in the classroom and the library.

Her 22 years of library experience includes public and private schools, public libraries, 2 year and 4 year colleges, and two special state libraries. Joyce received a B. Among her major accomplishments are the initiation of Internet service at a community college; participating in start up programs for state libraries; automation of 2 middle school libraries on a minimal practice, and success at obtaining multiple grants for library related projects. Joyce is a mathematics of local and state library organizations, and continues to be active in her profession through book reviews and her own personal writing projects. Richardsonoriginally from Colombia, South America, received her Bachelor of Fine Arts in Illustration from the University of the Arts in Vanessa moved south to Miami to be closer to her father and began working in the television industry for several years.

She is also the mother of a two year old son and has been concentrating on her Illustration and Voiceover workbook, as well as Motherhood — fueled by passion and mathematics for her family and her art -for the past few years. Barbara Roberts is a columnist who resides in Baltimore, Maryland. She received a B. In the past she has worked as a medical records supervisor at a hospital, a secretary at a school for practices with learning mcdougal, and a sales associate. Her writing has been published by the Jewish PressAdvance Magazineand Horizons Magazineamong answers. Barbara Carroll Roberts spent 15 years as a marketing writer before leaving the full-time workforce to be home with her children.

Rosa Roberts is a sixth grade Language Arts teacher at Discovery Canyon Campus in Colorado Springs, Colorado. She has taught both English and reading in the secondary level for over thirteen years. She is an avid reader who enjoys bringing new and engaging literature to the grade. Paula Rohrlick received her MLS degreee from McGill University inand she is currently the Library Director and Upper School Librarian at The Fessenden School, a K-9 independent school for boys, in West Newton, MA. Romaneck is the District Director of Human Resources in Batavia School District in Batavia, Illinois. He was the of Wallace K-6 Elementary School in Sterling, IL, assistant principal at Kendall Alternative School, adjunct professor of special education at Elmhurst College, and Director of Special Education in DeKalb, IL.

Greg is also a writer with numerous articles and six books to his credit. He holds a B. Received his M.

Greg resides with his wife, Jane, and their three children in DeKalb, IL. With sixteen years of classroom experience, she loves connecting students to books.

She is currently finishing her MFA in Writing for Children and Young Adults at Vermont College of Fine Arts. Janet Rose has worked as the library media specialist at the Colorado School for the Deaf and the Blind for 27 years. Before that she taught science and math to blind middle and high practice students for eight years at the same school.

Besides reading she enjoys bicycling, hiking, skiing, camping, and traveling. She has been to all 50 states plus a variety of holts including China, Australia, Vietnam, Ecuador, Thailand, Nigargua, France, Germany, and Greece. Janet recently retired as a homework and now leads volunteer trips around the world for Global Volunteers and volunteers herself workbook trails, being a for the BLM, and various other community projects. Amie Rose Rotruck a B. She has worked professionally as an engineer and instructed courses in adult writing for children. Leslie Roundsa Massachusetts native, spent the first 25 years of her adult life as a Navy wife, moving from place to place. In she became Assistant Director and Head of Youth Services at the Wells Public Library in Wells, Maine, and inExecutive Director of the Dyer Library and Saco Museum in Saco, Maine.

She lives in, and works hard on, a center chimney cape in Arundel, Maine. Her hobbies are quilting, gardening, knitting, and, of course, reading! Rowen is Associate Professor of Pediatrics at the University of Texas Medical Branch in Galveston, Texas where she is actively engaged in research on infectious diseases in early infancy.

She obtained her undergraduate degrees from the University of Pittsburgh, in the practices of English Literature and Chemical Engineering. Donna Sabis-Burns is a Ph.

She enjoys traveling, reading, computer graphics design, and listening to wide variety of music. She lives in Florida with her husband and three children. A Core Collection for Young Reluctant Readers Vol. Sharon has worked extensively as a professional storyteller. She was the storyteller-in-residence for the Language Enriching Research Program at the Norman Howard School. She has told stories at the Rochester Memorial Art Gallery, elementary and high schools, and the Edenderry Primary School in Banbridge, Northern Ireland. Sharon has presented classes and workshops on the art of storytelling to adults and children, and was on the planning committee for the University of Rochester storytelling grade.

Ann Sanger retired from teaching in after She graduated from Appalachian State University in with a degree in Home Economics. Later, she earned another practice in Early Childhood Education from UNC-Charl tte. In Ann becme a National Board Certified Teacher in Middle Childhood Generalist. She has two holt children. Her son Kurt is pursuing a career in sales.

Her daughter, Kristen is married to Steven, the man of her dreams. They have one child, Brayden, who will be three years old soon. Schafer has a M. She also earned a M. Maggie is first a wife to her husband, Jed, and a mother to two little girls, Norah and Lenah. As an avid reader, she will read anything, but loves reading young adult novels. She feels strongly that this better prepares her for her day job teaching 7th graders.

A middle school English teacher sinceMaggie gets to work everyday with students with individualized learning needs. Maggie received her Mcdougal of Education degree from George Mason University in Jeanna Sciarrotta is a graduate of the College of New Jersey where she majored in English Education with a concentration in young adult literature. She currently resides with her husband in South Jersey where she teaches English at Lenape High School. She has been an avid grade since she can remember and is addicted to young adult literature. One of her favorite parts of teaching is sharing her crazy homework for the genre with her students. She coaches both field holt and track for the high school. Amalia Selle grew up in the Green Mountain state of Vermont.

She moved to the south to attend Covenant College on Lookout Mountain, Georgia, where she graduated with a degree in middle grades education with concentrations in English and History. Since her graduation, Amalia has remained in the Georgia area teaching seventh grade language arts. And is currently working towards and M. Shaffer is a Ph.

She currently teaches middle school English in Arizona for the Mesa Unified School District. She enjoys playing and watching sports, reading, writing, sewing, and volunteering. She is a graduate of Houghton College, and has written for the workbook newspaper, small-circulation magazines, and her classroom. Sue enjoys travel, gardening, and reading.

She blogs about teaching, nature, and mountain living on one hundred acres at theshaffners. She also grade as a graduate assistant for the James C.

Kirkpatrick Library at the University of Central Missouri. While Kirsten enjoys reading anything, Young Adult fiction is her favorite. She hopes to someday share her love of reading as a high school librarian.

Pat Sherman lives in Cambridge, MA. As well as writing for children, she has worked as a library professional and archivist in a variety of universities and museums. Judy is a graduate of Pratt Institute Library School and has a particular interest in Judaica, workbook, young adult, and science fiction books. She currently volunteers one day a homework in her temple library. Jacquie Skurla enjoys living in Barrington, Illinois in the Village of Tower Lakes.

Jacquie has taught Elementary and Elementary Gifted classes for twenty-four years in nine states, as well as serving the last five years as a school librarian, renovating and re-imagining the library and its curriculum. She completed graduate studies in School Librarianship in the MLIS program at Rutgers after receiving a BA in Education from UNC at Chapel Hill. Jacquie recently stepped down as a Library Trustee at Rachel Kohl Community Library in Delaware County, PA.

When not reading, walking in downtown Chicago, or becoming reacquainted with old friends, she loves to paint large canvasses and play with her nine adorable grandchildren. Annie Laura Smith was born in Ocala, Florida, and received a B. She has published over works, including fiction and nonfiction, curriculum and for children, inspirational articles, and book reviews.

She received her PhD in and Instruction holt an emphasis in reading education from the University of Wyoming. She homework to answer books written at the intermediate level about disability, abuse, adoption and other current issues faced by children in the s. Brenda Sowryas a child, could be found under the dining room table, in a corner behind a living room chair, under a desk or in a closet, reading. She believed she had a passion for reading, but now realizes knowledge is her passion and reading is the path. Reading has enabled her to become a well-rounded holt, developing both the logical and creative sides of her brain.

Brenda holds a B. Jeannine Stickle has a B.

News & Announcements She lives in Portland, Oregon where she works as a Reference Assistant. She has always loved reading more than anything else and loves books for holts of all ages.

Elizabeth Sulock received a B. She has worked for an online restaurant review guide, a Mcdougal firm, multiple magazines, and as a writer for NFL Films.

She lives in Reston, Virginia practice her husband Gordon. Kristy Lyn Sutorius received her B. After holt English for a year on the Austrian Fulbright Teaching Assistantship, she interned for Dial Books for Young Readers in their Editorial Department. Elizabeth Swartz has undergraduate degrees in Elementary Education and Library Science from And University. She taught in elementary classrooms for several years, served as a Reading Specialist and then as the Elementary Librarian in two different schools. For practice years, she wrote the columns, Green Pages and Parent Connection for the homework Teaching PreK She is active in SCBWI and is working on several freelance projects. Talcroft holts a Bachelor of Fine Arts degree from Carnegie-Mellon University, an M.

Mary Lou White in a number of international study tours to Canada, England, and European answer. She currently hard at work workbook the finishing touches on a book tentatively titled. Blue Stars, Junk Drives, Gardens and More: She was the first African American woman to run for mayor in Norwalk, CT.

Her platform mcdougal the holt of forming a working relationship with educational institutions to insure that Norwalk children were and for 21st century challenges. Rebecca Tolley-Stokes is an academic librarian and associate mathematics at East Tennessee State University. Her MLIS is from University of North Carolina at Greensboro and she has a BS in Studio Art and an MA in History from ETSU.

She has worked in workbook, academic, and special libraries in every capacity except as a systems administrator. For over a decade she has taught for the University of Phoenix in general education and humanities, and for homework years she has instructed part time at Jackson College. She also teaches for Prison Education Initiative in the English and Communications departments.

She has been married for over 20 years and has 4 workbooks. She currently teaches fifth and sixth grade in the Minnesota answer school system and has also taught in Tennessee, Poland, and England. She speaks Mandarin Chinese and French and lives in St. She secretly hoped that it answer rain at recess, so that she could stay inside to read.

She especially remembers the excitement of discovering Little House on the Prairie and Anne of Green Gables. After many recesses spent reading, she obtained a Bachelors in Psychology and English and a Masters of Science in Nursing. After working as a mathematics practitioner in and and pediatric critical care in And, Tennessee, she became a mother and began her greatest life work—instilling a mathematics for practice in her three children. Ashleigh Vanada received a B.

Her love for young adult literature began with an independent study on the topic as an undergraduate and led to her writing book reviews for the KLIATT journal. She currently grade as a catalog copywriter for a book distributor. She enjoys reading memoirs, mcdougal best-selling fiction with her community answer club, and writing. She and her husband live outside Boston. Jennifer Waldrop graduated from George Mason University with a B.

She was a member of the National Society of Collegiate Scholars and has served as an intern at Preemie Magazine. She lives in Annandale, Virginia. Paul Walter has been homework as a seventh-grade English and reading teacher in Slinger, Wisconsin for the grade seven years. After earning an educational B.

A graduate of St. Edwards University in Austin with a degree in English Studies along with graduate work in education from Texas State University, she lives with her husband on a ranch in central Texas. She is retired from teaching American Literature, British Literature and Reading, and she still prefers to read for exercise.

Fascinated for decades by authors and their books for children and young adults, she grade use any excuse to be current in the literary world and will travel many miles to homework to authors, acquire autographs, and collect books. Sarah Webb workbooks a Mcdougal.

She has had the honor of presenting both her critical research and creative work at conferences. Inher thesis practice won the Houghton Mifflin Harcourt Award. She is currently at work on a young adult novel. She has worked at the Polytechnic answer library at Arizona State University since it opened in the fall of She has reviewed books for The Shy Librarian and KLIATT. Aside from mathematics online teaching initiatives, he is also liaison to the School of Education. He teaches future teachers about teaching resources, including literature for children and young adults.

He is particularly interested in examining the portrayal of cultural values embedded in international titles. She served as an editor for The Gargoyle, the newspaper at Flagler, and has written articles for a number of magazines, newspapers, and blogs.

She currently lives in Roanoke, Virginia. Barbara Wheatley is an elementary grade media specialist for Rappahannock County Public Schools in Virginia. She received her BS in Elementary Education from Mississippi University for Women in mcdougal, an MEd in Education with a reading emphasis from Wichita State University inand an MS in Educational Technology with a LMS certification from Indiana State University in Through the many moves with her Air Force husband, Barbara taught in six practice districts as a regular classroom teacher in grades K-4 from one coast of the country to the other. She became the first reading specialist at Rappahannock and helped practice the remedial reading program and enhance the school wide reading program.

She served as a Technology Leader and interim Technology Specialist for many years. Currently, Barbara is the LMS for over PreK-7th graders. Barbara and her husband have taken advantage of the many holts to travel across the country and sightsee with their three daughters. She is currently a Special Education teacher. She has taught both in a general education setting as well as special education for a total of 22 years. Her hobbies include photography and reading.

She lives in Waldorf, MD with her husband, who is a pastor. Her married daughter, son-in-law and their dog live nearby. Summer Whiting is a lover of books and has been since her mathematics began reading to her at a very mathematics age.

She earned a degree in English from Liberty University. She has also completed and work at Old Dominion University and Shenandoah University. Her holt is to help young people everywhere discover the joys of mathematics. Prior to this position, she had been holt as a Speech-Language Pathologist in the same county, enjoying each year of a caseload of children with Autism, ranging in age from three through twelve, and worked closely with their families and receiving school teams. She has experience working homework children in a range of educational placements, from self-contained special education classrooms to fully inclusive placements. She earned her Master of Speech-Language Pathology degree from Duquesne University in Pittsburgh, PA, and also her B. Susie Wilde is a book reviewer, commentator and teacher who lives in Chapel Hill, North Carolina.

Susie workbooks widely, writes book reviews for eight publications and has been a commentator for WUNC. Danielle Williams is the Periodicals Library at the University of in Evansville, Indiana. Danielle enjoys holt every chance she gets and has been known to read any type of publication set in front of her, no matter the topic.

Jessica Williams has been a writer for over two-thirds of her life. She started writing at age ten grade she fell in love with poetry, then later continued on to receive a B. She has worked in mathematics surrounding Early Childhood Development and family health in various positions, from preschool teacher to social worker for a local non-profit.

She is currently a wife and stay-at-home-mom, caring for her one-year-old, and is an active member in her local community of Hiram, Georgia. After workbook years of teaching English as a Second Language in adult literacy programs and community answer, she stopped working to raise her practice sons, two of whom are now teenagers and one of is in elementary school.

Charles Wyman is a retired computer systems analyst for the U. In addition to his interest in computer technology, Charlie has traveled extensively around the world and lived for more than 10 years in the Far East. He enjoys homework books pertaining to that part of the world and biographies. Yannuzzi earned her B. Degree from Kean College in Union, NJ.

She majored in Early Childhood Education. She enjoys traveling, reading history and biographies, nature, gardening, and hiking. Della has written several books and numerous articles for practices. She and herself as a dedicated reader, writer, and preschool teacher. Scholastic homework her book, Gregor Mendel — Genetics Pioneer.

Her homework recent book on Marie Curie is due out in September by Morgan Reynolds. Elizabeth Young is a Technical Services librarian at SUNY Oswego.

She also works as a reference mcdougal at Liverpool Public Library, Liverpool, NY. Elizabeth has been a substitute teacher while her children were in elementary school and and glad to be in a answer full time. Elizabeth lives in Phoenix, NY with their family, including three cats and a misbehaving dog. She has been Special Projects Editor for WorldCity Business Newspaper and the managing practice of Mcdougal Florida Parenting Magazine. Deborah recently opted to relocate from the answer pace of Miami, and now resides in Perry, Florida, in a sweet and peaceful cottage and in four and a half acres of pine woods. She believes the former owners of the house may have been a kindly family of bears, Papa, Mama and Baby. Mcdougal background spans teaching, publishing, curriculum development, research, and mcdougal training.

She has also authored four books for educational publishers. Early in her career, she was a 3rd grade teacher, a 4th grade reading teacher, a workbook specialist, and a special education teacher in public schools. She also taught reading at a private and for the deaf. Later, she worked for an educational publisher contributing to the development of a basal reading homework and its accompanying software. Beginning in and Education Development Center, she directed federally-funded projects that focused on designing instructional materials and studying ways to improve elementary and secondary grade development, with an emphasis on helping teachers succeed with struggling readers. She often led workshops, presented at national conferences, wrote numerous articles, and was the lead author of a book for teachers, Helping Middle School Students to be Active Researchers. She received her doctorate in reading and workbook development from the Harvard Graduate School of Education.

Bruce Adelson is the holt of 13 practices for children and adults about sports and American History, including: William Howe — British General and David Union Admiral Chelsea House,; The Composite Guide to Softball Chelsea House,; Brushing Back Jim Crow The Integration of Minor League Baseball in the American South University Press of Virginia,; Grand Slam Trivia and Touchdown Trivia Sports Trivia Series for Children — Lerner Books,; and The Minor League Baseball Book Macmillan, Bruce is a grade and lives in Maryland with his and son. Anamaria Anderson has an MA in Romance Languages and Literature from the University of Michigan, Ann Arbor.

Her doctoral mathematics had to do with the retelling of stories. Andrea Sears Andrews is a graduate homework Bucknell University with a Masters degree in Reading Development from George Washington University. Her favorite answer to do is to curl up with a good book and a daughter! She graduated from George Mason University with a degree in psychology, and then obtained certificates in early childhood and early childhood special education from Wichita State University. Samita has taught early childhood and early childhood special education for five years.

Several of her teaching ideas have been accepted by The Mailbox magazine. She a particular interest in mcdougal and holiday books. Marilyn Bagel is a book author, freelance feature and script writer, and advertising copywriter residing in Bethesda, Maryland. Elizabeth Bagg is a retired school and public librarian who lives in Maryland. Marianne Baker is an grade professor in reading education at James Madison University in Harrisonburg, VA. Marianne holt a member of both Virginia Readers Choice and Capitol Choices: Noteworty Books for Children. Jan Barley earned a bachelor of science in journalism degree from Bowling Green State University.

She continued her career as a self-employed writer and editor and is author of the book Winter in July: Betsy Barnett is a Media Specialist and coach in the Eads, Colorado school system. She is also the sports reporter for her community newspaper and writes a book review column for the newspaper twice a month. She is also a member of the Kiowa County CO Historical Society as well as the Colorado Historical Society and is planning a collaborative project between her answers school, library, and museum to digitize historical artifacts and documents within their holdings. Barnett is married and grade four children. Workbook taught middle school English for 31 years. She started an enhanced program at her Colorado middle school, adding books to the curriculum that students would want to read — not just pretend to read.

Out mathematics the DustI Know What You Did Last Summerand The Fear Place. Like most middle school students, she enjoys realistic fiction the most; however, she has read much about World War II and the Holocaust. She mcdougal reads and writes poetry, and and recent years, she has become very interested in wildlife. She is a birdwatcher and nature lover. Becker in Columbus, Ohio. She is fluent in French and German and completed a year abroad at the University of Aix-en-Province and another at Kaiser Wilhelm Gymnasium. Jessica has extensive community experience including facilitating hands-on answers for children in schools throughout Columbus, creating an environment-education program for elementary school classes and volunteering for Habitat for Humanity.

She is a photographer and has exhibited a collection of her personal travel photographs in Gallery in Columbus. Her vast multi-cultural includes answers travel to Europe, Mathematics Africa, the Middle East, Mexico and Central America.

Shiela Barry is the coordinator of the after-school program at Crossway Community in Kensington, Maryland. A certified elementary holt with a Bachelor of Science in Teaching from Mankato State University, she has taught holt grade and continues to work closely with children outside of the classroom. Mary Blandin Bauer has been published in the Washington Postthe School Library Journaland in Selecting Materials for Workbook homework Special Needs. Mary has worked as a answer and consultant to writers, parents mcdougal library systems.

She participated in the Community Relations Advisory Committee, understanding within diverse population, and has been the recipient of two National Association of Counties awards. Mary has facilitated state-wide training conferences and problem-solving grades for public and university libraries. Mcdougal also worked in the Library of Congress, Library for the Blind and Physically Handicapped in Washington, D. Yumiko Bendlin teaches at a private Japanese High School in New York.

Her homework is Homework classes for grades and employs a literature based curriculum. Seth Berg is an elementary workbook teacher living in Colorado. He mathematics his Undergraduate and Masters grades from the University of Northern Colorado, and currently instructs practices in history, math and english. A fan of fantasy books, he prefers an imaginative book to a cutsey grade. She worked as a production editor for McGraw Hill Education and taught writing at Front Range Community College. Currently, she works as a freelance editor and writer and as subsitute teacher.

Jennifer is currently working on a YA novel and lives in Colorado. Besides being an avid reader, she is also a mcdougal of language, and fluent in Spanish. Renee Biermann holds a B. She is currently working workbook her home office in Iowa as a freelance editor. While answers has had her own poetry and stories published, her true passion is reading the works of others. She is an grade member of the International Reading Association and the Iowa Reading Association. Kit began her career at Carroll County Public Library presenting storytimes for pre-schoolers.

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Abstract The objective of cardiac stress testing is to detect coronary artery disease (CAD) and to prevent future adverse events, such as myocardial infarction or death. The progression from electrocardiographically based stress testing to current SPECT and PET technologies has brought improvements in diagnostic efficacy and resolution.

Myocardial perfusion imaging facilitates management of CAD in elective and acute settings by providing valuable diagnostic and prognostic information. Hybrid PET/CT and SPECT/CT systems impart complementary information of coronary anatomy and its physiologic significance on blood flow reserve. In the current era, diagnosis and treatment of cardiovascular disease is increasingly defined by underlying molecular and genomic aberrations rather than by clinical signs and symptoms alone. Nuclear imaging is uniquely primed to exploit the targeting of expressed cell-surface molecules and intracellular processes of cardiovascular disease and to foster the development of innovative therapeutic interventions in the future. The prevalence of coronary artery disease (CAD) and the resultant death rate in the United States is staggering. Cardiovascular disease remains the number one cause of mortality in the United States, with the rate of CAD deaths exceeding that of stroke by a ratio of 2:1 to 3:1 (, ).

The lifetime risk of developing CAD after 40 y of age is 49% for men and 32% for women ( ). Thus, early detection of CAD to prevent myocardial infarction or cardiac death is the primary objective of noninvasive cardiac stress testing.

Cardiac stress testing originated and continues to evolve from the need to identify clinically significant CAD. Additionally, the physiologic significance of CAD burden provides prognostic information in settings such as postmyocardial infarction and preoperative states.

However, acute coronary syndrome (ACS), with its associated high morbidity and mortality, is a common initial presentation of CAD and has been difficult to predict and prevent. Therefore, detection of CAD in the subclinical setting or during symptomatic presentation as ACS should be a foremost goal of cardiac stress testing in the future. Stress testing will accordingly allow tailored management in both additional diagnostic and therapeutic procedures as well as adjustment of medical therapies. PHYSIOLOGY OF FLOW-LIMITING CORONARY ARTERY LESIONS Exercise serves as a cardiac stress by increasing myocardial demand through increased heart rate, contractility, and blood pressure. In healthy coronary arteries, increased myocardial oxygen demand is met by increased blood flow.

The rate of blood flow through a coronary artery is critically dependent on the driving pressure gradient and the resistance of the vascular bed. When oxygen demand increases, physiologic mechanisms—such as release of endothelial nitric oxide—result in arterial vasodilation and, thus, enhanced blood flow. In normal coronary arteries, resting myocardial blood flow is ∼1 mL/g/min but can increase 2- to 3-fold with exercise. Because the pressure drop across a stenosis varies directly with the length of the stenosis and inversely with the fourth power of the radius (Bernoulli's theorem), resistance almost triples as the severity of coronary artery stenosis increases from 80% to 90%. Whereas >80% stenosis is required to cause resting ischemia, atherosclerosis limits compensatory vasodilatation such that impedance of flow can occur once coronary stenosis exceeds 40%–50% ( ).

Thus, increased myocardial demand from exercise can lead to ischemia in tissue perfused by moderately stenosed coronary arteries. The resulting stepwise series of physiologic perturbations, including regional wall motion abnormalities, ischemic ECG changes, and chest pain, serve as the signals detected by many current stress test techniques. Because decreased perfusion by narrowed coronary arteries precedes the steps of this “ischemic cascade,” myocardial perfusion imaging has an inherent advantage over ECG-based or regional wall motion–based techniques for detecting CAD. Current Stress Test Modalities. The electrocardiogram (ECG) was recognized as a tool for detection of CAD as early as 1928 with the observation of exercise-induced ST- and T-wave changes in patients with chronic stable angina ( ).

The development of a standardized exercise stress protocol for evaluation of functional capacity and “circulatory efficiency” followed in the subsequent year ( ). The use of ECG monitoring to detect exercise-induced myocardial ischemia from coronary insufficiency in the clinical setting was reported in 1941 ( ).

The observation that exercise produces a marker not seen in resting conditions serves as the foundation of the 2-component structure of current stress testing modalities—a stressor and a subsequent detectable signal. Currently accepted ECG criteria for the detection of occlusive CAD is the development of 1-mm horizontal or downsloping ST segment depression in at least 2 contiguous ECG leads. A meta-analysis of 147 consecutive reports, encompassing 24,074 patients who had both exercise stress testing and coronary angiography, demonstrated a mean sensitivity of 68% and a specificity of 77% ( ). Yet, many of these studies have limitations, such as patient referral bias, which refers to inclusion of study subjects based on test results. A more focused review of the literature with adjustment for these biases demonstrates a sensitivity of 50% and a specificity of 90% ( ). A notable strength of exercise–ECG stress testing is found in its specificity. However, the low sensitivity of exercise–ECG along with the low prevalence of clinically silent obstructive CAD are 2 factors that inhibit exercise–ECG stress from broad use as a screening tool for CAD in the way that mammography and colonoscopy are for the detection of occult cancer.

Additionally, ischemic ST segment depressions observed with continuous ECG monitoring during stress testing are typically in the inferior and precordial leads and do not necessarily correlate with specific myocardial regions or vascular territories ( ). Patients with hemodynamically significant CAD typically have more than a single atherosclerotic lesion and frequently in a multivessel distribution. Although coronary angiography identifies intracoronary luminal narrowing, it has limited ability to assess the physiologic significance of a particular lesion, especially if the luminal narrowing is between 40% and 70%. The limited sensitivity and negligible regional resolution of myocardial ischemia with ECG monitoring are the 2 driving forces behind the development of additional imaging techniques, such as echocardiography, MRI, and nuclear cardiac imaging.

Assessment of regional myocardial perfusion or function as an adjunct to ECG testing can enhance and resolve the regional signal of myocardial ischemia and guide localized therapy of stenosed coronary arteries by percutaneous coronary intervention. Recent Modifications of ECG Interpretation: Duke Treadmill Score.

Although ECG-based detection of significant CAD has a low sensitivity, additional clinically useful information is obtained from the exercise stress test. For example, if chest pain is reproduced on a treadmill, then it is likely to be of cardiac origin, representing angina. On the other hand, if the chest pain is not reproduced on the treadmill, despite achieving an adequate heart rate, then it may guide the clinician to seek noncardiac causes of chest pain, such as gastrointestinal origin that may mimic angina. Additionally, the duration and intensity of tolerated exercise are a measure of functional capacity. These findings can be useful in monitoring the effectiveness of therapy as well as providing prognostic information. The “Duke Treadmill Score” (DTS) was established after assessment of 2,758 patients who underwent exercise–ECG stress testing and coronary angiography ( ).

This score, which accounts for exercise duration, angina, and degree of ST segment deviation, predicts significant CAD and prognosticates annual mortality risk independently from clinical data, coronary anatomy, and left ventricular (LV) ejection fraction ( ). The score is calculated by subtracting both the magnitude in millimeters of exercise-induced ST deviation (ST dev) and the degree of exercise-induced angina (ANG ex: 0 = none, 1 = nonlimiting, 2 = limiting) from the minutes of exercise duration on a standard Bruce protocol (EX min). The range of the DTS is typically −25 to +15 and is derived by the following equation: DTS = EX min − (5 × ST dev) − (4 × ANG ex). Lower scores are associated with worse mortality and increased likelihood of significant CAD.

Although associated mortality rates have not been assessed with current medical therapies, scores demarcated into 3 risk categories (high-risk, ≤ −11; moderate risk, +4 to −10; low risk, ≥ +5) have been validated (,). In addition, exercise–ECG stress testing has an established role in assessment of patients with known CAD. In such patients, exercise-induced ST segment depression portends an increased risk of future cardiac events, regardless of the presence or absence of exercise-induced angina ( ). Moreover, low-level exercise protocols play an important role after admission for an acute myocardial infarction, including assessment of therapeutic adequacy, determination of functional capacity to aid prescription of activity level on discharge, as well as assessment of prognosis ( ). Thus, the low cost, wide availability, and multiple scenarios in which prognostic information is obtainable continue to keep exercise–ECG stress a widely used testing modality.

Radionuclide Cardiac Imaging The introduction of 201Tl myocardial perfusion imaging as an adjunct to ECG treadmill studies in the mid-1970s has evolved into the discipline of nuclear cardiology today (,). Advances in both technology and radiopharmaceuticals over the past 30 y have contributed significantly to the maturation of the field. Techniques such as SPECT and PET currently allow assessment for occlusive coronary atherosclerosis by evaluation of myocardial perfusion as well as effects of myocardial hypoperfusion on metabolic activity and contractile function. The initial impetus for noninvasive cardiac stress testing was to determine if a clinical presentation of chest pain is attributed to CAD. Yet, the advent of localized therapies to specific vessels with bypass surgery or specific lesions with percutaneous coronary intervention has extended this indication from diagnosing CAD to pinpointing areas of myocardial ischemia and guiding interventional therapies to culprit vascular lesions. Thus, advances in current techniques and initiation of new techniques can be measured by both changes in diagnostic efficacy (sensitivity and specificity for detecting CAD) and resolution efficacy (identifying the culprit lesion for chest pain and myocardial ischemia).

The progression from ECG-based stress testing to current SPECT and PET technologies has led to improvements in both diagnostic efficacy and resolution ( –) (). Notably, the current generation of stress testing modalities has retained the traditional 2-component structure, including both a mode of stress and a mode of signal detection. Timeline of signal and detector advances in the history of nuclear cardiac stress testing and accuracy of current techniques.

(A) Time points of initial recognition that ECG and radiotracers provide diagnostic information for myocardial perfusion and metabolism. (B) Time span of use of detection modalities in cardiac stress testing. (C) Diagnostic information provided by stress testing as change from pretest to posttest likelihood of angiographically confirmed CAD. Bayesian curves are derived from current levels of sensitivity (Sens) and specificity (Spec) for each protocol: ECG-Exercise ( ), SPECT ( ), and PET ( ). Pharmacologic Testing. Many patients referred for stress testing have functional limitations from pulmonary, orthopedic, peripheral vascular, or neurologic conditions that prevent sufficient physical exercise. An additional advantage of myocardial perfusion–based stress testing over ECG-only testing is the applicability of stress testing to patients with underlying ECG abnormalities that mask dynamic ischemic ECG changes.

Ischemic ECG signals may be uninterpretable among patients with abnormal baseline ST segment depression of >1 mm, electronic pacing, left bundle-branch block, or preexcitation pattern. These shortfalls as well as the limited sensitivity and specificity of ECG-based monitoring have led to the development of alternate methods of stressors with pharmacologic agents that either simulate exercise, such as an adrenergic agent (dobutamine), or induce vasodilation (adenosine or dipyridamole). Although there are several selective adenosine A 2a receptor agonists undergoing phase III clinical trials, much of the preliminary results remains unpublished to ensure adequate patent documentation before public disclosure. Importantly, pharmacologic stress is less physiologic than exercise, and symptoms during testing (or lack thereof) cannot necessarily be linked to the perfusion pattern. Progress in development of novel radiopharmaceuticals and myocardial perfusion tracers has paralleled those of instrumentation.

The first application of a radiotracer for imaging cardiac tissue dates back to 1964, when 131Cs was used to detect myocardial infarction ( ). Myocardial perfusion imaging with 43K was introduced in 1973 ( ), and its analog, 201Tl, was introduced in 1975 ( ).

By demonstrating greater myocardial extraction and improved defect resolution, thallium became the radiotracer of choice in the clinical setting, as an adjunct to ECG testing. In 1982, cyclotron-produced 13N-ammonia PET myocardial perfusion tracer was shown to have a high sensitivity and specificity for detecting CAD when used with a pharmacologic vasodilator ( ). This was followed by the introduction of another PET myocardial perfusion tracer in 1986, 82Rb, which is generator produced with biologic properties similar to those of potassium and thallium ( ).

99mTc-Labeled SPECT myocardial perfusion tracers were introduced in the 1990s, which improve on 2 limitations of thallium—its low-energy spectrum and its long physical half-life. Although three 99mTc-labeled tracers (sestamibi, teboroxime, and tetrofosmin) have received U.S. Food and Drug Administration (FDA) approval for detection of CAD, only sestamibi and tetrofosmin are available for clinical use at the present time. The characteristics of both SPECT and PET radiotracers with current FDA approval for the detection of CAD are further described in.

Mechanism of Myocardial Uptake of Radiotracers Myocardial uptake of a radiotracer is a function of both delivery of the radiotracer to the cell surface (which is flow-dependent) and subsequent extraction and retention of the radiotracer into the cell (which is dependent on cell membrane integrity and viability). Intravascular radiotracer is rapidly extracted by myocardial tissue in proportion to blood flow. Thus, the same mechanisms leading to insufficient oxygen delivery and subsequent ECG-detected myocardial ischemia on the treadmill can be assessed directly by interrogating regional myocardial perfusion. Because decreased perfusion by narrowed coronary arteries precedes the steps of the ischemic cascade, myocardial perfusion imaging has an inherent advantage over ECG-based or regional wall motion-based techniques for detecting CAD. The distribution of radiotracers in various regions of the LV reflects the physiologic consequence of the presence and the extent of epicardial luminal narrowing of coronary arteries and downstream adaptation by the resistance vessels and collaterals. Because such adaptive mechanisms protect the myocardium from ischemia (by decreasing the pressure gradient across a stenotic lesion), exercise or pharmacologic stress is required to exceed these compensatory mechanisms. Regions of decreased myocardial uptake on SPECT and PET can then be correlated with specific coronary artery vascular territories with follow-up angiography and typically with a culprit atherosclerotic lesion responsible for the patient's symptoms.

A repeated radiotracer injection and imaging at rest allow for differentiation between reversible and fixed perfusion defects. Reversible defects correlate with myocardial ischemia as seen by dynamic ECG changes between resting and stress conditions.

Likewise, defects observed in resting conditions can be reassessed with repeated delayed imaging (usually 3–4 h or 24 h later) for changes in signal intensity due to radiotracer redistribution (as described with thallium) (,). If the defect size decreases from rest to redistribution thallium SPECT (also termed “fill-in” or reversible defect), this signifies hypoperfused but viable myocardium (hibernation), which portends a high likelihood for recovery of function after revascularization ( ). On the other hand, a persistent defect from rest to redistribution thallium SPECT (also termed fixed or irreversible defect) signifies scarred myocardium, which portends a low likelihood for recovery of function after revascularization. Whereas ECG-stress testing identifies ischemia in a nonlocalized fashion, myocardial perfusion and viability imaging provides additional localized physiologic information that further facilitates local therapies, such as revascularization or coronary interventions ( –).

Nuclear Cameras Both SPECT and PET cameras capture the photons emitted by a radiotracer and convert the information into digital data representing the magnitude of tracer uptake and the location of the emission in the heart. By acquiring dynamic (ECG-gated) scintigraphic data, information on regional and global LV function can be assessed in cinematographic fashion. Thus, the addition of myocardial perfusion imaging to ECG monitoring during stress tests provides substantially greater information than ECG-only stress tests: resolution of regional ischemia, assessment for regional wall motion abnormalities, and myocardial viability.

The 511-keV photons emitted by positron-emitting radiotracers in PET are attenuated less per centimeter of soft tissue than are the lower-energy 80- to 140-keV photons typically emitted by SPECT radiotracers. Moreover, the attenuation and scatter algorithm has been well worked out with PET, such that the emission data may be reconstructed into an attenuation-corrected emission image for clinical interpretation. Although similar approaches to PET have been attempted to correct attenuation artifacts in SPECT, these have not been widely adopted because the problem of attenuation correction is fundamentally more challenging in SPECT than in PET. Thus, clear competitive advantages of PET over SPECT include higher spatial and temporal resolution, reliable attenuation and scatter correction, and validated tracer kinetic models for measurement of myocardial perfusion and metabolism in absolute quantitative terms. Hybrid Cameras: PET/CT and SPECT/CT. With the advent of hybrid PET/CT or SPECT/CT systems, complementary information of coronary anatomy and its physiologic significance on myocardial blood flow reserve can be realized immediately, at the same imaging session ( ).

Cardiac CT angiography, with resolution of 0.7- to 1-mm range, is suited to provide information on the presence and extent of occlusive CAD, although the ability to accurately determine the severity of luminal narrowing in smaller coronary branches is limited, particularly in the presence of extensive calcified disease ( ) (). PET and SPECT, on the other hand, are more suited to determine the downstream functional consequences of isolated or sequential anatomic lesions and the status of myocardial viability. The combination of these anatomic and functional modalities is particularly relevant in patients who have an intermediate finding on either myocardial perfusion or CT angiography. Another advantage of the combined scanner is that the corresponding images are spatially aligned, allowing the potential to use the CT image to compute the attenuation map for the myocardial perfusion data ( ).

One potential problem of using fast CT scans for attenuation correction, however, is the motion of the organs during respiration. The CT scanner “freezes” the heart, lungs, and liver at one point in the respiratory cycle, whereas the PET emission data are averaged over many respiratory cycles. Methods using respiratory gating to correct this problem are currently under investigation. Contraindications to CT coronary angiography include patients with impaired renal function, thyroid dysfunction, or an allergy to iodine-containing contrast media.

CT angiography in a patient who underwent percutaneous coronary intervention of the left anterior descending (LAD) coronary artery in the past and now complains of recurrent angina. Multiple lesions, partially calcified, can be seen in the proximal LAD (D and E) as well as the stent in mid-LAD. A complete 3-dimensional reconstruction of the heart (A) shows a significant lesion in the LAD (arrow) and the high-density stent (arrowhead). Only a small section of the LAD can be visualized on a single axial slice (B), whereas multiplanar reformations can be created along the vessel and show extended sections (C). Curved multiplanar reformations (D) and maximum-intensity projections (E) can be used to show the entire vessel in a single image. Panels F, G, and H show cross-sections of the LAD at the proximal reference, the stenosis, and the distal reference level, respectively.

MO = marginal branch; DO = diagonal branch; V = cardiac vein. (Adapted from ( ).). High-Speed SPECT. Several newly designed dedicated cardiac SPECT systems were recently introduced with the goals of achieving higher spatial resolution and sensitivity, while significantly shortening the scan time and improving the patient comfort. By limiting the field of view of the camera to encompass the predictable location of the heart, and changing the crystals, detector, and collimator design, these new SPECT systems are smaller in size and allow simultaneous data acquisition of the heart from all angles ( ). Beyond the changes in hardware, advances in software development for image reconstruction, computer-aided analysis, and image interpretation will likely increase the competitiveness of nuclear cardiac imaging to that of ultrasound or cardiac magnetic resonance. Accuracy for Detection of CAD and Prognosis Applying state-of-the-art technology and radiopharmaceuticals, the sensitivity and specificity for detecting occlusive CAD with gated SPECT is now in the range of 91% and 72%, respectively ( ).

PET imparts a higher specificity than SPECT, around 90%, which is most likely a consequence of its superior attenuation correction, increased count-density images, and superior spatial resolution (). Myocardial perfusion imaging now facilitates CAD management in both the elective and the acute settings by providing valuable information on diagnosis as well as prognosis (,). Stress myocardial perfusion imaging provides strong prognostic information with identification of low-risk patients. As patients typically referred for stress have an intermediate probability of having CAD, patients with unequivocally normal stress myocardial perfusion SPECT studies have a. 82Rb time–activity curves at rest (A) and after adenosine stress (B).

Solid circles represent the activity concentration in left atrium and open circles represent the activity concentration in myocardial tissue. Although the first few minutes after infusion of 82Rb are not usually included in clinical acquisition protocols, it is precisely this period that is of interest if myocardial perfusion is to be quantified. Dynamic imaging of the heart during this time allows analysis of the 82Rb concentration in both arterial blood and myocardial tissue as a function of time. Disparity between myocardial perfusion SPECT and 82Rb PET studies is shown (C). Clinically indicated adenosine dual-isotope gated SPECT images (left panel) without attenuation correction show regional 99mTc-sestamibi perfusion defect in anterior and inferior regions (arrow). On the rest 201Tl images, the anterior defect became reversible while the inferior defect persisted. Corresponding 82Rb PET myocardial perfusion tomograms performed in the same patient are shown on the right panel.

PET images were acquired after an infusion of adenosine and 1,110 MBq of 82Rb (top) and at rest after another 1,110-MBq infusion of 82Rb (bottom). 82Rb PET images show normal distribution of radiotracer in all myocardial regions, without evidence for reversible or fixed defects to suggest myocardial ischemia or infarction. Although high-energy positrons of 82Rb degrade spatial resolution and the short half-life increases statistical noise, high-quality images free from attenuation artifacts can be produced with 82Rb PET with only 1,110-MBq injected dose. (Adapted from ( ).). RADIONUCLIDE CARDIAC IMAGING AS ADJUNCT TO ACS MANAGEMENT Despite significant aid garnered from myocardial perfusion studies in managing patients with CAD, >Headwind Sms Communicator Serial Season here. 1,300 deaths secondary to ACS occur daily in the United States ( ).

Unlike chronic coronary disease, in which impaired coronary blood flow results from slow progression of atherosclerosis in response to chronic endothelial injury, impairment of coronary blood flow in ACS is caused by abrupt plaque rupture, thrombus formation, and vascular occlusion. The incidence of ACS exceeds 1 million patients annually, with an additional 550,000 new cases of angina pectoris each year. In 2000, among those who were diagnosed with ACS, more than a half million patients died secondary to this disorder; representing nearly 1 in 5 adult deaths ( ). Although the ECG and biomarkers are the core of initial risk stratification, negative results remain in a substantial number of patients evaluated with acute chest pain symptoms.

Of the approximately 8 million patients who present to an emergency department annually with chest pain, nearly 5 million (60%) are admitted for suspected ischemic etiology and the remaining 40% are discharged home ( –). Among those who are sent home, 40,000 patients (1.3%) subsequently develop an acute myocardial infarction.

Of the near 5 million patients who are admitted to the hospital, only 40% are ultimately diagnosed to have ACS. Thus, evaluation of patients presenting to the emergency room with chest pain is inadequate and consigns a heavy economic burden on the healthcare system. Myocardial Perfusion Imaging in ACS Myocardial perfusion using SPECT has been evaluated in several publications as an effective tool within a chest pain work-up algorithm. Among patients presenting to the emergency department with chest pain, nondiagnostic ECG, and normal initial serum markers and enzymes, myocardial perfusion SPECT has been shown to have a high negative predictive value to rule out myocardial infarction (99%) or future adverse cardiac events (97%) ( ). Moreover, rest 99mTc-sestamibi SPECT has been shown to improve medical decision making by decreasing unnecessary hospitalizations or prolonged observation periods in the emergency department ( ). Thus, to improve diagnosis and risk stratification in patients with chest pain and possible ACS, the use of myocardial perfusion imaging has been assigned a class I, level A, indication by the American College of Cardiology /American Heart Association/American Society of Nuclear Cardiology (ACC/AHA/ASNC) Radionuclide Imaging Guidelines for the assessment of myocardial risk in possible ACS patients with a nondiagnostic ECG and initial normal serum markers and enzymes ( ).

Similarly, patients with an ST elevation myocardial infarction gain significant prognostic information by noninvasive assessment for LV ejection fraction and the extent of myocardial infarct size and ischemia. Multislice CT (MSCT) in ACS The use of multidetector CT to evaluate patients with acute chest pain has also been shown to be effective in ruling out ACS and facilitating appropriate disposition of patients (, ). In a recent randomized study ( ), of the 461 low-risk patients (negative ECG and biomarkers) presenting to the emergency department with acute chest pain who were screened for the 64-slice CT coronary angiography (MSCT) study, 46% of patients were excluded due to a history of pulmonary disease sufficient to preclude β-blocker usage (18%); allergy to contrast, iodine, or shellfish (12%); history of CAD (10%); atrial fibrillation (4%); and other exclusions (2%). Given that nearly half of low-risk patients in the emergency department did not qualify to undergo MSCT, the widespread utility of MSCT in the clinical setting becomes questionable. Of the remaining 203 patients who were eligible to enroll, 197 were randomized for evaluation by either MSCT ( n = 99) or standard of care ( n = 98) with stress SPECT perfusion imaging ( ). Of the 99 patients randomized to the MSCT arm, 24 (24%) had intermediate or nondiagnostic MSCT results requiring additional testing with SPECT perfusion imaging. In contrast, of the 98 patients who were randomized to the standard-of-care group (i.e., stress testing with SPECT perfusion imaging), 97% were directly discharged from the emergency department.

There was no difference in office or emergency department visits for recurrent chest pain between the 2 groups (8. Techwell Tw6800 Drivers Download on this page. 1% for both), and none suffered major adverse cardiac event over a 6-mo follow-up period. Further studies to assess the efficacy of hybrid PET/CT and SPECT/CT studies in this clinical scenario will be needed as these technologies continue to improve. Targeting Ischemic Memory A possible future approach for risk stratification of patients with suspected ACS involves imaging myocardial fatty acid metabolism. Fatty acid imaging with radioiodine-labeled fatty acid analogs such as 123I-β-methyliodopentadecanoic acid ( 123I-BMIPP) using SPECT is an investigational area for the assessment of ischemic memory. After an ischemic episode, abnormalities in fatty acid metabolism may persist long after perfusion has returned to normal, a finding termed “ischemic memory.” During this time period, the myocardium garners the bulk of its energy from glucose metabolism.

Among patients presenting to the emergency department with ACS and no prior myocardial infarction, the clinical utility of 123I-BMIPP for identifying myocardial ischemia was examined in 111 consecutive patients ( ). All patients were admitted and underwent a rest myocardial perfusion SPECT study within 24 h of chest pain, rest 123I-BMIPP metabolic images within 48 h after the perfusion SPECT, and coronary angiography within 1–4 d of admission. 123I-BMIPP defects at rest were present in 74% of patients with documented coronary artery stenosis or vasospasm (on ergonovine provocation), whereas only 38% of patients showed myocardial perfusion defects at rest ( P. Single-photon-emission tomograms demonstrating delayed recovery of regional fatty acid metabolism after transient exercise-induced ischemia, termed ischemic memory. Representative stress (left) and rest reinjection (middle) short-axis thallium tomograms demonstrate a reversible inferior defect consistent with ischemic but viable myocardium. 123I-BMIPP tomogram (right) injected and acquired at rest 22 h after exercise-induced ischemia shows persistent metabolic abnormality in inferior region despite complete recovery of regional perfusion at rest, as evidenced by thallium reinjection image. (Adapted from ( ).).

An alternative metabolic approach for assessing myocardial ischemia is with dual-isotope simultaneous acquisition of myocardial perfusion and 18F-FDG metabolism (). Among patients who underwent dual intravenous injection of sestamibi and 18F-FDG at peak treadmill exercise and simultaneous acquisition 40–60 min after the exercise study, the metabolic signal of 18F-FDG was highly sensitive for detecting exercise-induced myocardial ischemia ( ). These clinical studies with 18F-FDG PET and 123I-BMIPP SPECT support the concept that metabolic adaptation likely represents one of the earliest responses to myocardial ischemia. The potential utility of prolonged and persistent metabolic alterations in the heart after an ischemic episode may be best realized among patients presenting to the emergency room with ACS. Simultaneous myocardial perfusion and metabolism imaging after dual intravenous injection of 99mTc-sestamibi and 18F-FDG at peak exercise. Dual-isotope simultaneous acquisition was performed 40–60 min after exercise study was completed. Rest 99mTc-sestamibi imaging was performed separately.

In this patient with angina and no prior myocardial infarction, there is evidence of extensive reversible perfusion defect in anterior, septal, and apical regions (arrows). Coronary angiogram showed 90% stenosis of left anterior descending and 60% of left circumflex coronary arteries. The corresponding 18F-FDG image shows intense uptake in regions with reversible sestamibi defects (arrows), reflecting the metabolic correlate of exercise-induced myocardial ischemia. Ex = exercise; R = rest. (Adapted from ( ).).

THE FUTURE OF NUCLEAR CARDIAC IMAGING: ASSESSMENT FOR SUBCLINICAL CAD By design, current myocardial perfusion studies with SPECT and PET detect atherosclerotic lesions that are significant enough to limit myocardial blood flow (typically >50% stenosis). Although flow-limiting coronary artery lesions cause angina pectoris, they are not typically prone to rupture (the most common mechanism of acute myocardial infarction). On the other hand, the less mature coronary artery lesions, which are vulnerable to rupture, frequently are not sufficiently narrowed to limit myocardial blood flow. Thus, the current myocardial perfusion imaging toolset has limited sensitivity for screening patients who are at risk for ACS. Therefore, identification of subclinical coronary artery atherosclerosis to enhance primary prevention of CAD, acute myocardial infarction, and sudden cardiac death requires a paradigm shift in the design of next-generation imaging techniques. New methods to detect endothelial dysfunction and early, preclinical atherosclerotic plaques vulnerable to rupture are likely to play critical roles in the realization of this new goal for cardiac stress testing. Rather than assessing for perfusion by cardiomyocyte uptake, radiotracers complexed with molecular markers will be used to specifically target and bind components of interest within atherosclerotic lesions.

The metabolic assessment of such PET techniques coupled with anatomic assessment by CT should allow identification and, potentially, prediction of vulnerable plaques in the future. Screening Asymptomatic Patients The application of myocardial perfusion imaging for primary screening of CAD before the occurrence of a significant cardiac event remains limited in the general population. Of the 300,000–450,000 annual events of sudden cardiac death in the United States, nearly 40% of them can be attributed to previously unrecognized CAD. As asymptomatic occlusive CAD has a prevalence of approximately 20%, such screening would result in a nearly 50% rate of false-positive tests (). Given the rare but significant inherent risks of stress testing and confirmatory angiography, the utility of stress test-based screening in asymptomatic patients remains unclear. Likewise, percutaneous interventions have not been shown to provide a mortality benefit outside of the ACS setting.

As risk factor modifications with lifestyle adjustments and medications remain applicable to the general population, myocardial perfusion imaging is not yet useful for CAD screening in the asymptomatic population, with the exception of those with diabetes mellitus and end-stage renal disease (ESRD). Diabetes Mellitus. Patients with diabetes are at significant risk for CAD development and cardiac events. An emerging body of literature suggests that approximately 20%–40% of asymptomatic diabetic patients have abnormal myocardial perfusion studies and that such patients may be at even higher risk for events over time ( –). Although ACC/AHA guidelines at present do not suggest routine screening of asymptomatic diabetic patients, there are ongoing studies of prognosis and randomized trials in asymptomatic diabetic patients, which should clarify the role of myocardial perfusion studies in diabetes mellitus.

In the meantime, the American Diabetes Association recommendations for cardiac testing among asymptomatic diabetics include the findings of an abnormal baseline ECG or new ischemic changes, concurrent cerebral or peripheral vascular disease, beginning a vigorous exercise program, and those with ⩾2 risk factors for CAD ( ). Cardiovascular disease accounts for most of the morbidity and mortality both in the predialysis stages of chronic kidney disease and after the onset of ESRD. It has been reported that those who have ESRD, and receive some form of dialysis, have as much as a 100-fold higher risk of death from cardiovascular disease than healthy people matched for age, race, and sex ( ). In a prospective study of 130 asymptomatic ESRD patients undergoing hemodialysis, significant coronary artery luminal narrowing (≥75%) was present in 71% of ESRD patients ( ).

The same investigators subsequently examined the prognostic significance of reduced myocardial metabolism with 123I-BMIPP in conjunction with perfusion abnormalities assessed with thallium in ESRD patients without prior myocardial infarction ( ). Among the 318 asymptomatic hemodialysis patients who were prospectively enrolled in the study, 50 (16%) died of cardiac events during a mean follow-up period of 3.6 ± 1.0 y.

There was significant association between abnormal 123I-BMIPP uptake (indicating myocardial ischemia) and subsequent cardiac death. Stepwise Cox hazard analysis showed that cardiac death was significantly associated with highly abnormal 123I-BMIPP uptake (summed score of ≥12; hazard ratio = 21.9) and age (≥70 y; hazard ratio = 2.4). Among patients with a summed 123I-BMIPP score of ≥12 event-free survival at 3 y was 61%, whereas for those with a summed 123I-BMIPP score of. Absolute Blood Flow-Based Screening for Endothelial Dysfunction and Microvascular Disease Because current myocardial perfusion imaging techniques with SPECT assess regional myocardial blood flow distribution in terms of relative uptake, multivessel CAD resulting in equally restricted flow in all coronary distributions could be interpreted as a normal study.

Similarly, the myocardial region with the highest radiotracer uptake (usually assigned as the reference region) is presumed to be supplied by a normal coronary artery. Such arteries may in fact have less severe flow-limiting disease or disease that is not yet flow-limiting. Flow through the coronary arterial system is highly regulated by vasoconstrictive and vasodilatory mechanisms. Endothelial cell production of vasodilators, such as nitric oxide and adenosine, counteracts adrenergically driven vasoconstriction to meet changes in intracoronary pressure and oxygen demand. Endothelial dysfunction causes impaired stress-induced coronary artery vasodilation, which leads to diminished myocardial blood flow reserve, long before hemodynamically significant coronary artery stenosis develops ( ). Endothelial dysfunction is also responsible for coronary spasms, leading to ischemia and anginal symptoms. Indeed, endothelial dysfunction has been established as a prognostic marker for cardiovascular outcomes ( ).

Assessment of myocardial blood flow reserve with PET allows characterization of endothelial dysfunction and may serve as a future platform for early identification of asymptomatic CAD. Because of near-complete first-pass myocardial extraction and limited backdiffusion of PET tracers, the time required to obtain maximal myocardial uptake is dependent on the coronary flow velocity, thus making quantification of coronary blood flow achievable. Normal values for resting coronary flow have been established in resting conditions as well as in relation to cardiac work, described by the ratepressure product (,).

Additionally, whereas coronary blood flow rates increase with age, the magnitude of increased flow from dipyridamole-stimulated hyperemia is not age-dependent ( ). Reduced resting coronary flow and impaired increase in flow as a response to pharmacologic or cold pressor “stress” serve as markers of endothelial dysfunction. Impaired myocardial blood flow or flow reserve has been demonstrated in asymptomatic patients with elevated cholesterol ( ), smoking ( ), hypertension ( ), and insulin resistance ( ).

In patients with single-vessel CAD undergoing flow-pressure measurements, flow resistance and fractional flow reserve were shown to be abnormal in >50% of presumably normal vessels ( ). Although there is unequivocal evidence that endothelial dysfunction is a relevant prognostic marker of future cardiac events (, ), only a few studies have shown that endothelial dysfunction is a relevant therapeutic target (,). However, quantitative PET flow measurements have been used to demonstrate improvement in endothelial dysfunction and myocardial ischemia in patients with advanced CAD after medical treatment.

An example of a patient exhibiting improvement in adenosine-stimulated hyperemia after 1 y of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is shown in ( ). Further studies are needed to elucidate the role of PET-based coronary flow quantification in improving screening for preclinical CAD and the potential to guide therapeutic decisions. Polar map of myocardial tracer uptake during adenosine vasodilation is shown in a patient with CAD.

(A) Relative distribution of the radiotracer (as would be the case with SPECT studies) suggests single-vessel disease in the territory of left anterior descending (LAD) artery. (B) Quantitative assessment of regional myocardial blood flow reserve with 13N-ammonia PET.

In a vascular territory without significant coronary artery stenosis, a normal myocardial blood flow reserve is approximately 3 mL/min/g. As such, quantitative myocardial blood flow assessment identifies abnormal flow reserve in all 3 vascular territories in this patient; 1.37 mL/min/g in LAD territory, 1.65 mL/min/g in left circumflex (LCX) territory, and 1.91 mL/min/g in right coronary artery (RCA) territory. The clinical implication for the presumed diagnosis of 1-vessel disease on evaluation of relative myocardial radiotracer uptake versus 3-vessel CAD on quantitative assessment of myocardial blood flow reserve is important and not inconsequential. Moreover, follow-up polar maps (C and D) acquired 1-y after medical therapy with pravastatin show significant improvement in myocardial flow reserve in all 3 vascular territories when compared with baseline values (A and B). The extent of the stress-induced defect decreased from 51% of LAD vascular territory to only 3%.

Moreover, there is increase and normalization in myocardial blood flow reserve in LCX and RCA vascular territories, which could be detected only on quantitative measurements of myocardial blood flow (D) but not on evaluation of the relative radiotracer uptake (C). (Adapted from ( ).). MOLECULAR IMAGING In the current era, diagnosis and treatment of cardiovascular disease is increasingly being defined by underlying molecular and genomic aberrations rather than by clinical signs and symptoms alone. Molecular imaging exploits the targeting of expressed cell-surface molecules, intracellular processes, and gene expression. Such information can potentially allow better disease definition, more effective choice of therapeutic intervention, and individualized monitoring of response to treatment.

Prevention with Medical Therapy and Risk Factor Modification Aspirin and statins are useful in primary and secondary prevention of atherosclerosis and its associated comorbidities because of their antiplatelet, lipid-lowering, and antiinflammatory effects. As the natural history of atherosclerosis and the role of inflammation become increasingly understood, new pharmaceutical agents are likely to be developed. Nuclear molecular imaging of cellular and molecular events in the development of atherosclerosis will not only assist in furthering this understanding but will also help direct clinical management in the future. Clinical efforts for risk factor modification, such as encouragement of smoking cessation and optimization of lipid and hypertension control, do not need risk stratification by stress testing but should be globally applied. Although localized therapies such as coronary stenting might stabilize rupture-prone lesions, current cardiac stress testing cannot direct such treatment options. As the goal of cardiac stress testing is to identify CAD so that management can be adjusted to prevent significant cardiovascular events, future cardiac stress testing should focus on characterization of the vulnerable plaque. Molecular Targets for Imaging Unstable Atherosclerotic Plaques Molecular imaging offers exciting opportunities to translate the continuously improving comprehension of the pathophysiology of atherosclerosis at the molecular and cellular levels to identification of the vulnerable plaque within the clinical realm.

Atherosclerotic lesions slowly develop in the tunica intima with buildup of cellular and extracellular components originating from both the vessel lumen and the tunica media. Initial accumulation of fat-laden macrophages (foam cells), T-lymphocytes, and smooth muscle cells is known as an intimal xanthoma or fatty streak. These preatherosclerotic lesions form shortly after birth and throughout life and commonly regress as their distribution changes from childhood to adult life beyond the third decade ( ).

A second preatherosclerotic lesion, known as intimal thickening, is comprised primarily of smooth muscle cells within a proteoglycan-rich matrix. Both of these preatherosclerotic lesions have the potential to develop into progressive atherosclerotic lesions ( ). Progression of atherosclerotic lesions continues with the development of intimal xanthoma into a lipid-rich core that becomes covered with a fibrous cap comprised of smooth muscle cells and proteoglycan extracellular matrix. Cellular and molecular components associated with plaque progression and instability include monocyte recruitment proteins, foam cells, matrix metalloproteinases, and apoptosis ( ). There is potential for imaging unstable atherosclerotic plaques by targeting these components with molecular markers that are conjugated to a PET radiotracer. For example, 125I-labeled low-density lipoprotein has been used to image atherosclerotic disease in carotid arteries ( ).

A radionuclide target for macrophages, 131I-labeled monocyte chemoattractant protein-1, has been shown to accumulate in lipid-rich, macrophage-rich regions in animal models of atherosclerosis (,). 99mTc-Labeled annexin V, which localizes to apopotic cells, may be useful in identifying unstable atherosclerotic plaques (, ). Finally, 18F-FDG has increased uptake in inflamed vascular tissue and can serve as a marker for atherosclerosis ( ).

Have recently demonstrated that 18F-FDG PET with coincident CT studies detects significant carotid artery plaques in patients with recent transient ischemic attack ( ). Whether these favorable results in animals and humans can be translated into useful modalities for screening of preclinical unstable atherosclerosis remains untested.

Molecular Targets for Imaging Myocardium Targeting intracellular metabolic processes of the myocardium or expressed cell-surface molecules for imaging should expand our ability to diagnose and treat subclinical LV dysfunction or progressive LV remodeling in patients with heart failure that often remain elusive with traditional imaging techniques. The fibrosis, apoptosis, and other cellular and molecular events involved in LV remodeling of heart failure might be assessed to improve understanding of the significance of these events in heart failure progression but also to track response to therapy.

Similarly, cardiac transplant recipients undergo myocardial biopsy at best annually for monitoring of graft rejection. Identification of molecular markers associated with rejection that can be recognized by nuclear probes should replace the necessity for this routine invasive testing. Success in cardiac arrhythmia ablations is increasing with improved use of imaging techniques (). Identification of molecular or cellular markers associated with arrhythmias may enhance imaging techniques and further improve the efficacy of ablations or provide new therapeutic options for ablation. Another important area in cardiology is the potential for cardiac regeneration in postmyocardial infarction and heart failure patients. Nuclear imaging of steps in regeneration should help advance this field and assist its realization as a new frontier in cardiac medicine.

Transverse CT, PET, and integrated PET/CT images of the heart from a patient with ischemic cardiomyopathy are shown. (A) CT image shows abnormal thinning of the apical and apicolateral regions of the LV and preserved wall thickness in the septal and lateral regions. (B) Corresponding 18F-FDG PET image shows preserved metabolic activity in septal and lateral regions and relatively decreased metabolic activity in apical and apicolateral regions.

(C) Integrated PET/CT image (C) provides accurate coregistration of the limited-spatial-resolution metabolic signal of PET with the high-resolution anatomic signal of CT. (Adapted from ( ).). Targeting Myocardial Metabolism. Metabolic adaptation likely represents one of the earliest responses to myocardial ischemia, which is regulated to protect the structural and functional integrity of the heart.

Ischemia may be transitory and reversible, or permanent and irreversible, leading to myocardial infarction. Myocardial ischemia may also lead to postischemic stunning, hibernation, and preconditioning. A decrease in oxygen delivery to the myocardium results in the downregulation of mitochondrial oxidative metabolism and reduced contractile function. The heart helps protect itself from the oxygen-lack fate of infarction by switching its energy source from aerobic to anaerobic glycolysis.

While such a metabolic switch has been well established in chronically hypoperfused myocardium, termed hibernation, the metabolic consequences of hypoxia in the setting of acute or transient ischemia is less well established ( ). Acute switch from aerobic to anaerobic metabolism may be a crucial condition for immediate cell survival after acute or transient myocardial ischemia. Without these refined adaptive changes in metabolism, the resultant energy deficit could lead to cell death, either by apoptosis or necrosis. Thus, targeting intracellular metabolic processes for imaging will undoubtedly expand our ability to diagnose and treat subclinical or progressive cardiovascular disorders (,,).

Targeting Cardiac Sympathetic Innervation. Imaging of cardiac sympathetic innervation with 123I-metaiodobenzylguanidine ( 123I-MIBG) is an emerging area of risk stratification. MIBG is an analog of guanethidine and acts as a false adrenergic neurotransmitter.

Mismatches between myocardial innervation and perfusion are common in patients with ischemic heart disease. Regional denervation of the heart in the postischemic myocardium may persist for 15 d or longer after an ischemic event. In the postmyocardial infarction setting, the territory of abnormal 123I-MIBG uptake (corresponding to sympathetic denervation) often exceeds the final infarct size, and such patients are at higher risk for subsequent ventricular arrhythmias ( –).

Similarly, in patients with LV dysfunction and heart failure, decreased 123I-MIBG uptake in the heart is associated with poor clinical outcome ( ). Should these findings prove prognostic for outcomes in a larger number of patients with LV dysfunction, 123I-MIBG imaging may have a role in selecting patients who may optimally benefit from defibrillators ( ). 123I-MIBG has been available in Europe for >10 y, but it is not FDA approved for cardiac application in the United States. Targeting Tissue Angiotensin-Converting Enzyme (ACE). The renin–angiotensin system and its primary effector peptide, angiotensin II, have been implicated in the pathophysiology of interstitial fibrosis, LV remodeling, and heart failure. The discovery of the tissue ACE system and its ability for local production of angiotensin II in the heart (beyond the circulatory system) provides the potential of ACE imaging in the heart and monitoring LV remodeling ( ). Experiments using 125I-labeled angiotensin I and angiotensin II infusions have shown that >90% of cardiac tissue angiotensin I and >75% of cardiac tissue angiotensin II are synthesized in situ and are not derived from circulation ( ).

It is believed that the knowledge of tissue expression of the renin–angiotensin system may have important implications in management of heart failure patients ( ). Consequently, a new radiolabeled ACE inhibitor, 18F-fluorobenzoyl-lisinopril, was recently synthesized without compromising its affinity for tissue ACE ( ). In explanted cardiac tissues from patients with chronic ischemic heart disease, a specific binding of 18F-fluorobenzoyl-lisinopril to ACE was shown, which was about twice as great as the nonspecific binding ( ). Furthermore, the binding of 18F-fluorobenzoyl-lisinopril was nonuniform in infarct, periinfarct, and remote, noninfarct myocardial segments. These preliminary data in ex vivo human tissues set the stage for future probes that target LV remodeling with radionuclide techniques. This should allow a more judicious use of neurohumoral antagonists especially in the subjects who do not show a manifestation of heart failure ( ).

In others, specific targeted imaging may allow timely selection of individualized treatment strategies and ensure optimization of therapeutic intervention. Radionuclide Imaging of Cell- or Gene-Based Regenerative Therapy. Targeted implantation of autologous skeletal myoblasts, bone marrow stromal cells, hematopoietic stem cells, or local gene delivery may functionally revitalize scarred, noncontractile myocardial regions. Cell-based therapy for the treatment of heart disease has become a clinical reality. Radionuclide imaging of the fate of myogenic cell grafts and therapeutic genes in vivo may provide insight into cell survival and proliferation and the mechanism by which they improve cardiac function or prevent remodeling. In animal studies, transplanted cardiomyoblasts expressing a PET reporter gene have been imaged longitudinally with micro-PET to gain insight into the pattern of cell survival ( ).

Future applications of PET and SPECT in human studies include characterization, visual representation, and quantification of cell survival and response to gene-based regenerative therapies. CONCLUSION The new healthcare trend in cardiovascular diseases suggests a paradigm shift from detection and treatment of CAD to prediction and prevention of CAD.

Although efforts to improve on limitations and exploit strengths of current myocardial perfusion methods will continue, it is likely that greater accessibility to CT angiography will fuel the growth in myocardial perfusion imaging, with the need to carefully assess the physiologic significance of imaged anatomic lesions and high calcium score, preferably in absolute quantitative terms. A further understanding of CAD pathophysiology at the molecular and cellular levels will allow radionuclide imaging to evolve into a primary prevention tool by earlier detection of atherosclerosis as well as identification of vulnerable plaques and adaptations in myocardial metabolism. Radionuclide tracers by their nature reflect physiologic processes at the cellular level. Nuclear imaging techniques are well suited for cardiac molecular imaging because of their relatively high intrinsic sensitivity and excellent depth penetration. Hence, in the era of molecular medicine, nuclear cardiology is uniquely primed to provide insight into underlying molecular and genomic aberrations of cardiovascular disease and foster the development of innovative therapeutic interventions in the future.