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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged bioengineering, Cardiovascular Disorders, computational biology, Coronary artery disease, DNA Sequencing, functional proteomics, gene expression, gene silencing, genetic engineering, Heart Failure, Human Genome Project, Hypertension, MicroRNA, mtRNA, myocardial infarction, nitric oxide, Nitric oxide synthase, Personalized medicine, protein modifications, Proteomics, reverse engineering, RNA, signaling pathways, Stem cell, synbiology on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

• Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
• Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
• Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
• Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
• Enable the discovery of new drugs in the continuing emergence of drug resistance.
• Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

http://synthetic_biology/Introduction_to_Synthetic_Biology_and_Metabolic_Engineering/Kristala_ L.J._Prather/E2/iBiology.htm#/sthash.71kZ0ofr.dpuf

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at

http://science360.gov/obj/video/753bb4fa-aafb-4315-848e-51066ed9799a/finding-way-kristala-l-jones-prather-phd 

Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

David Bartel: micro-RNAs

 

I. Introduction to microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=dupzE66J8u4#t=0

– See more at: http://www.ibiology.org/ibioseminars/genetics-gene-regulation/david-bartel-part-1.html#sthash.nGGr1tIt.dpuf

II. Regulatory Effects of Mammalian microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ#t=0

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240

1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.

In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

• In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
• Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Posted in Cardiovascular Pharmacogenomics, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Ionic Transporters Na+, K, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged ATO2A@, ATPase, Aviva Lev-Ari, CAD, Coronary artery disease, Coronary circulation, coronary microvascular dysfunction, eNOS, genetic polymorphisms, Heart disease, Heart Failure, Hebrew University of Jerusalem, ion channels, ischemic heart diases (IHD), KCN5A gene (Kv1.5 channel), Kir6, Myocardial Ischemia, Nav 1.5, non-modifiable protective factor, NOS encoding, rs5215_GG, rs5219_AA, SCN5A, Thomas C. Südhof, voltage-gated K ion channel on December 21, 2013| Leave a Comment »

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Image created by Adina Hazan 06/30/2021

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival. 

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/advanced-medicineprize2013.pdf

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/18/physiologist-professor-lichtstein-chair-in-heart-studies-at-the-hebrew-university-elected-dean-of-the-faculty-of-medicine-at-the-hebrew-university-of-jerusalem/

4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

• Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock

Aviva Lev-Ari, PhD, RN

• Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Aviva Lev-Ari, PhD, RN

•  Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

• Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

See References to articles at the end of this article on

• ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

• Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux

• Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

• Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
• single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
• ion channels acting in vascular smooth muscle and/or
• endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

• the whole coding region of KCN5A gene (Kv1.5 channel).

The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

• to identify individuals at relatively low-risk for cardiovascular disease
  
• an independent protective role of the
  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy  e-mail:francesco.fedele@uniroma1.it
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4
This article is published with open access at Springerlink.com

Abstract

Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

• a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

• activity of specific ion-channels, and
• key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

• ion-channels expressed in the coronary vasculature and the possible
• correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

• analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

• polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

• IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

• influencing the susceptibility for microvascular dysfunction and (IHD,
• independent of the presence of classic cardiovascular risk factors: atherosclerosis   

http//dx.dio.org/10.1007/s00395-013-0387-4

Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease

 Introduction

Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

• endothelial dysfunction and
• atherosclerosis [11, 53, 65, 67].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

• atherosclerotic disease and
• myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

• endothelial,
• nervous,
• neurohumoral,
• myogenic, and
• metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

• ATP-sensitive potassium (KATP) channels,
• voltage-gated potassium (Kv) channels,
• voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

• coronary smooth muscle and endothelial cells, which
• modulates the degree of contractile tone in vascular muscle and
• the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

• the endothelium and vascular smooth muscle cells of coronary arterioles
• to the perpetually fluctuating demands of the myocardium for blood flow
  [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

• the clinical relevance and 
• causes of microvascular dysfunction in IHD. 

By altering the overall

• regulation of blood flow in the coronary system,
• microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

• contribute to microvascular dysfunction [29, 60]. But
• ion channels play a critical role in microvascular endothelial
• and smooth muscle function.
  

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

• microvascular dysfunction and 
• myocardial ischemia, 

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

• IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
• ion channels acting in vascular smooth muscle and/or
• endothelial cells of coronary arteries.

Discussion

Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

• In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
• In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
• The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

• hypertension = 17 %,
• T2DM = 34.1 %,
• dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

• rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
• and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

• inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
• rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

• confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

• to identify individuals at relatively low-risk for cardiovascular disease,
• regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

• endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

• NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via

• activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

• an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
• association of this SNP with CAD in Asian populations [74]. In addition,
• this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

• variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].

Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

• high-grade coronary stenosis or occlusion [19].

As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells

• potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].

Several types of K+ channels are expressed in the coronary tree.

• The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
  [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
• Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.

K-ATP channel activation results in an outward flux of potassium and

• consequent hyperpolarization, resulting in
• voltage-gated calcium channel closure,
• decreased Ca2+ influx, and ultimately
• vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

• an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

• structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

• concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

• may have originated in a common ancestor, further indicating a
• possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

• rs5215_GG against developing CAD and
• a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
• The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
  the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening

• are both impaired in diabetes mellitus [39].

It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,

• independent of the presence of either diabetes mellitus or dyslipidemia.

These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,

• regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

• future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

• pergolide [25],
• 4-amino-pyridine [32], and
• correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

• cardiac metabolic demand and
• coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

• the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

• our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

• catalyzes the hydrolysis of ATP coupled with the
• translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

• genetic variants of SERCA and the
• prevalence of microvascular dysfunction or IHD.

Conclusions

This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients

• with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.

Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

• the precise manners by which specific genetic polymorphisms affect ion channel function and expression

have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.

2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.

3. There is a lack of ethnic diversity of our cohort.

4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.

5. There is a lack of functional characterization of the described genetic polymorphisms.

6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

• sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
• in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

• typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).

Methods

In this prospective, observational, single-center study – 242 consecutive patients admitted to our department were enrolled with

• the indication to undergo coronary angiography .

All patients matched inclusion criteria

1. age [18];
2. suspected or documented diagnosis of acute coronary syndrome or stable angina
3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

1. previous allergic reaction to iodine contrast,
2. renal failure,
3. simultaneous genetic disease,
4. cardiogenic shock,
5. non- ischemic cardiomyopathy

All patients signed an informed consent document  –

prior to participation in the study, which included

• acknowledgement of the testing procedures to be performed
  (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

1. both endothelium-dependent microvascular function
   [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
2. nonendothelium-dependent microvascular function
   [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

• the 242 patients were divided into three groups (see also Fig. 1).

1. Group 1: 155 patients with anatomic coronary alteration
   (comprising patients with acute coronary syndrome and chronic stable angina).
   • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
   • after IC infusion of acetylcholine and adenosine].
2. Group 2: 46 patients with functional coronary alteration
   [normal coronary arteries as assessed by angiography, and
   • as assessed by angiography and with normal functional tests
     (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
3. Group 3: 41 patients with anatomically and functionally normal coronary arteries

 

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

• related to ion channels and/or reported to be associated with
• microvascular dysfunction and/or myocardial ischemia and/or
• diseases correlated to IHD, such as diabetes mellitus.

Polymorphisms for the following genes were analyzed:

1. NOS3 (endothelial nitric oxide synthase, eNOS),
2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
3. SCN5A (voltage-dependent Na+ channel,
4. Nav1.5),
5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

• exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
• the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
• four previously described variants [26, 47, 71, 72].

We also examined

• the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

• the prevalence of SNPs in genes encoding  several effectors (including ion channels)
• involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

• a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
  undergoing coronary angiography,

we estimated that

• a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
  • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

• analysis of multiple inheritance models for SNPs were also tested
  (co-dominant, dominant, recessive, over-dominant and log-additive)
• using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
• designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

• with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

• the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
• using a free web-based application  (http://213.151.99.166/index.php?module=Snpstats) [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

• were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

• one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

• the independent impact of genetic polymorphisms on
  • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

• genetic polymorphisms on coronary artery disease
  and microvascular dysfunction,

while adjusting for other confounding variables.  The following parameters were entered into the model:

• age,
• male gender,
• type 2 diabetes mellitus (T2DM),
• systemic arterial hypertension,
• dyslipidemia,
• smoking status, and
• family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

• into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

• fasting levels of glucose of >126 mg/dL in two separate measurements or
• if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

• systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
• in two separate measurements or
• if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

• serum cholesterol levels were>220 mg/dL or
• if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.

Results

Sixty-two polymorphisms distributed among six genes coding for

• nitric oxide synthase,
• the SERCA pump, and
• ion channels
  • were screened for sequence variations using PCR amplification and
  • direct DNA sequencing analysis

in the population of

• 155 patients with CAD (group 1),
• 46 patients with microvascular dysfunction (group 2), and
• 41 patients with normal coronary arteries and
  • normal endothelium dependent and endothelium-independent vasodilation (group 3).

In Group 3, the genotype distribution of

• SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).

In Group 1 (CAD), the polymorphism

• rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).

The genotypic distribution of groups in terms of polymorphisms for

• eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5

were noticed. However, significant differences (p.05) for the SNPs

• rs5215_GG, and
• rs5219_AA of Kir6.2/KCNJ11 were observed,

as shown in Table 2. 

Table 3 displays significant differences between normal subjects (group 3) and

• patients with either CAD (group 1) or microvascular dysfunction (group 2).

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

• significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
• a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

• in microvascular dysfunction for rs5219 AA. In contrast,
• rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

SOURCE for TABLES

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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3. Belardinelli L, Shryock JC, Fraser H (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor
ranolazine. Heart 92:6–14. doi:10.1136/hrt.2005.078790
4. Berwick ZC, Moberly SP, Kohr MC, Morrical EB, Kurian MM, Dick GM, Tune JD (2012) Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-
flow autoregulation. Basic Res Cardiol 107:264. doi:10.1007/s00395-012-0264-6
5. Brayden JE (2002) Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 29:312–316. doi:10.1046/j.1440-1681.2002.03650.x
6. Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378. doi:10.1152/physrev.00032.2008
7. Chen TT, Luykenaar KD, Walsh EJ, Walsh MP, Cole WC (2006) Key role of Kv1 channels in vasoregulation. Circ Res 99:53–60. doi:10.1161/01.RES.0000229654.45090.57
8. Cohen KD, Jackson WF (2005) Membrane hyperpolarization is not required for sustained muscarinic agonist-induced increases in intracellular Ca2+ in arteriolar endothelial
cells. Microcirculation 12:169–182. doi:10.1080/10739680590904973
9. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gu¨nter K, Goedel-Meinen L (1990) Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium
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SOURCE for References 1-75

Basic Res Cardiol (2013) 108:387   http://dx.doi.org/10.1007/s00395-013-0387-4

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ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

Posted in CABG, Cardiac and Cardiovascular Surgical Procedures, tagged Cardiovascular Disorders, Coronary artery bypass surgery, Coronary artery disease, Heart disease, William Nugent on November 5, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

We decided to include ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery in this Scientific Journal as a Reference resource to all our Experts, Authors, Writers.

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SOURCE

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

http://circ.ahajournals.org/content/100/13/1464.long

• ACC/AHA Practice Guidelines

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)

1. Committee Members

1. Kim A. Eagle, MD, FACC, Cochair;
2. Robert A. Guyton, MD, FACC, Cochair;
3. Ravin Davidoff, MB, BCh, FACC;
4. Gordon A. Ewy, MD, FACC;
5. James Fonger, MD;
6. Timothy J. Gardner, MD, FACC;
7. John Parker Gott, MD, FACC;
8. Howard C. Herrmann, MD, FACC;
9. Robert A. Marlow, MD, MA, FAAFP;
10. William Nugent, MD;
11. Gerald T. O’Connor, PhD, DSc;
12. Thomas A. Orszulak, MD;
13. Richard E. Rieselbach, MD, BS, FACP;
14. William L. Winters, MD, FACC;
15. Salim Yusuf, MB, BS, PhD

1. Task Force Members

1. Raymond J. Gibbons, MD, FACC, Chair;
2. Joseph S. Alpert, MD, FACC;
3. Kim A. Eagle, MD, FACC;
4. Timothy J. Gardner, MD, FACC;
5. Arthur Garson Jr, MD, MPH, FACC;
6. Gabriel Gregoratos, MD, FACC;
7. Richard O. Russell, MD, FACC;
8. Thomas J. Ryan, MD, FACC;
9. Sidney C. Smith Jr, MD, FACC

Key Words:

• ACC/AHA Practice Guidelines
• bypass
• angioplasty
• morbidity
• mortality
• revascularization
• risk factors

Next Section

I. Introduction

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines was formed to make recommendations regarding the appropriate use of diagnostic tests and therapies for patients with known or suspected cardiovascular disease. Coronary artery bypass graft (CABG) surgery is among the most common operations performed in the world and accounts for more resources expended in cardiovascular medicine than any other single procedure. Since the original Guidelines were published in 1991, there has been considerable evolution in the surgical approach to coronary disease, and at the same time there have been advances in preventive, medical, and percutaneous catheter approaches to therapy. These revised guidelines are based on a computerized search of the English literature since 1989, a manual search of final articles, and expert opinion.

As with other ACC/AHA guidelines, this document uses ACC/AHA classifications I, II, and III as summarized below:

Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or efficacy of a procedure.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful.

Previous SectionNext Section

II. Outcomes

A. Hospital Outcomes

Seven core variables (priority of operation, age, prior heart surgery, sex, left ventricular [LV] ejection fraction [EF], percent stenosis of the left main coronary artery, and number of major coronary arteries with significant stenoses) are the most consistent predictors of mortality after coronary artery surgery. The greatest risk is correlated with the urgency of operation, advanced age, and 1 or more prior coronary bypass surgeries. Additional variables that are related to mortality include coronary angioplasty during index admission; recent myocardial infarction (MI); history of angina, ventricular arrhythmias, congestive heart failure, or mitral regurgitation; and comorbidities such as diabetes, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and renal dysfunction. Table 1⇓ shows a method by which key patient variables can be used to predict an individual patient’s operative risk of death, stroke, or mediastinitis.

B. Morbidity Associated With Bypass Surgery

1. Neurological Events

Neurological impairment after bypass surgery may be attributable to hypoxia, emboli, hemorrhage, and/or metabolic abnormalities. Postoperative neurological deficits have been divided into 2 types: type 1, associated with major, focal neurological deficits, stupor, or coma; and type 2, in which deterioration in intellectual function is evident. Adverse cerebral outcomes are observed in ≈6% of patients after bypass surgery and are equally divided between type 1 and type 2 deficits. Predictors of cerebral complications after bypass surgery include advanced age and a history of hypertension. Particular predictors of type 1 deficits include proximal aortic atherosclerosis as defined by the surgeon at operation, history of prior neurological disease, use of the intra-aortic balloon pump, diabetes, hypertension, unstable angina, and increased age. Predictors of type 2 deficits include a history of excess alcohol consumption; dysrhythmias, including atrial fibrillation; hypertension; prior bypass surgery; peripheral vascular disease; and congestive heart failure. Estimation of a patient’s risk for postoperative stroke can be calculated from Table 1⇓.

2. Mediastinitis

Deep sternal wound infection occurs in 1% to 4% of patients after bypass surgery and carries a mortality of ≈25%. Predictors of this complication include obesity, reoperation, use of both internal mammary arteries at surgery, duration and complexity of surgery, and diabetes. An individual patient’s risk of postoperative mediastinitis can be estimated from Table 1⇓.

3. Renal Dysfunction

Postoperative renal dysfunction occurs in as many as 8% of patients. Among patients who develop postoperative renal dysfunction (defined as a postoperative serum creatinine level >2.0 mg/dL or an increase in baseline creatinine level of >0.7 mg/dL), 18% require dialysis. Overall mortality among patients who develop postoperative renal dysfunction is 19% and approaches two thirds among patients requiring dialysis. Predictors of renal dysfunction include advanced age, a history of moderate or severe congestive heart failure, prior bypass surgery, type 1 diabetes, and prior renal disease. Table 2⇓ can be used to estimate the risk for an individual patient. Patients with advanced preoperative renal dysfunction who undergo CABG surgery have an extraordinarily high rate of requiring postoperative dialysis. Among patients with a preoperative creatinine level >2.5 mg/dL, 40% to 50% require hemodialysis.

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Table 2.

Risk of Postoperative Renal Dysfunction (PRD) After Coronary Artery Bypass Graft Surgery

C. Long-Term Outcomes

Predictors of poor long-term survival after bypass surgery include advanced age, poor LVEF, diabetes, number of diseased vessels, and female sex. In some studies, additional predictors include angina class, hypertension, prior MI, renal dysfunction, and clinical congestive heart failure. Predictors of the recurrence of angina, late MI, or any cardiac event also include obesity and lack of use of an internal mammary artery, as well as those factors identified above. Of these events, the return of angina is the most common and is primarily related to late vein-graft atherosclerosis and occlusion.

Previous SectionNext Section

III. Comparison of Medical Therapy Versus Surgical Revascularization

The comparison of medical therapy with coronary surgical revascularization is primarily based on randomized, clinical trials and large registries. Although clinical trials have provided valuable insights, there are limitations to their interpretation in the current era. Patient selection had primarily included individuals ≤65 years of age, very few included large cohorts of women, and for the most part, the studies evaluated patients at low risk who were clinically stable. In addition, because the studies were done in the late 1970s and early 1980s, only 1 of the trials used arterial grafts, and even that trial had no arterial grafts in 86% of patients. Newer modalities of cardioprotection during cardiopulmonary bypass were not used, nor were minimally invasive or off-bypass techniques. Finally, medical therapy was not optimized in the trials. Lipid-lowering therapy had not yet become standard, aspirin was not widely used, and β-blockers were used in just half of the patients. Angiotensin-converting enzyme inhibitors were not being routinely used in patients with congestive heart failure or dilated cardiomyopathy. Accordingly, although the clinical trials have provided important insights, their interpretation must be viewed with caution, given the evolution in all types of coronary therapies.

For the most part, stratification of patients in the trials was based on the number of vessels with anatomically significant disease, whether or not the major epicardial obstruction was proximal, and the extent of LV dysfunction as determined by global EF. The end point of the trials was primarily survival.

Overview: Randomized Trials

There were 3 major, randomized trials and several smaller ones. A collaborative meta-analysis of 7 trials with a total enrollment of 2649 patients has allowed comparison of outcomes at 5 and 10 years (Tables 3⇓, 4⇓, and 5⇓ and the Figure⇓). Among all patients, the extension survival of CABG surgical patients compared with medically treated patients was 4.3 months at 10 years of follow-up. The benefit of CABG compared with medical therapy in various clinical subsets is presented below.

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Figure 1.

Extension of survival after 10 years of follow-up in various subgroups of patients, from a meta-analysis of 7 randomized studies. LV indicates left ventricular; VA, Veterans Administration.

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Table 3.

Total Mortality at 5 and 10 Years

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Table 4.

Subgroup Results at 5 Years

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Table 5.

Subgroup Analysis of 5-Year Mortality by Risk Stratum

1. Left Main Coronary Artery Disease

The trials defined significant left main coronary artery stenosis as a >50% reduction in lumen diameter. Median survival for surgically treated patients was 13.3 years versus 6.6 years in medically treated patients. Left main equivalent disease (≥70% stenosis in both the proximal left anterior descending [LAD] and proximal left circumflex arteries) appeared to behave similarly to true left main coronary artery disease. Median survival for surgical patients was 13.1 years versus 6.2 years for medically assigned patients. The benefit of surgery for left main coronary artery disease patients continued well beyond 10 years. By 15 years, it was estimated that two thirds of patients originally assigned to medical therapy and who survived would have had surgery. The 15-year cumulative survival for left main coronary artery disease patients having CABG surgery was 44% versus 31% for medical patients.

2. Three-Vessel Disease

If one defines 3-vessel disease as stenosis of 50% or more in all 3 major coronary territories, the overall extension of survival was 7 months in CABG patients compared with medically treated patients. Patients with class III or IV angina, those with more proximal and severe LAD stenosis, those with worse LV function, and/or those with more positive stress tests derived more benefit from surgery.

3. Proximal LAD Disease

In patients with severe, proximal LAD stenosis, the relative risk reduction due to bypass surgery compared with medical therapy was 42% at 5 years and 22% at 10 years. This was even more striking in patients with depressed LV function.

4. LV Function

In patients with mildly to moderately depressed LV function, the poorer the LV function, the greater was the potential advantage of CABG surgery. Although the relative benefit was similar, the absolute benefit was greater because of the high-risk profile of these patients.

5. Symptoms and Quality of Life

Improvement in symptoms and quality of life after bypass surgery parallels the outcome data regarding survival. Beyond survival, bypass surgery may be indicated to alleviate symptoms of angina above and beyond medical therapy or to reduce the incidence of nonfatal complications like MI, congestive heart failure, and hospitalization. Registry studies have shown a reduction in late MI among highest-risk patients, such as those with 3-vessel disease, and/or those with severe angina. In pooled analyses, a benefit on the incidence of MI was not evident. This result likely reflected an early increase in MI perioperatively after CABG, which was balanced by fewer MIs over the long term among CABG recipients. Antianginal medications were required less frequently after bypass surgery. At 5 years, two thirds of bypass patients were symptom-free compared with 38% of medically assigned patients. By 10 years, however, these differences were no longer significant. This result is related to the attrition of vein grafts in the bypass group as well as crossover of medically assigned patients to bypass surgery.

6. Loss of Benefit of Surgery

After 10 to 12 years of follow-up, there was a tendency for the bypass surgery and medical therapy curves to converge, in regard to both survival as well as nonfatal outcomes. This convergence is due to a number of factors. First, the reduced life expectancy of patients with coronary disease (regardless of treatment) leads to a steady attrition. Second, the increased event rate in the late follow-up period of surgically assigned patients was likely related to the progression of native coronary disease and graft disease over time. Finally, medically assigned patients crossed over to surgery late, thus allowing the highest-risk medically assigned patients to gain from the benefit of surgery later in the course of follow-up. By 10 years, 37% to 50% of medically assigned patients had crossed over to surgery. Tables 3⇑, 4⇑, and 5⇑ and the Figure⇑ provide estimates of long-term outcomes among patients randomized in the trials. These tables and the Figure⇑ can be used to estimate the general survival expectations in various anatomic categories.

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IV. Comparison of Bypass Surgery With Percutaneous Revascularization

The results of a number of randomized, clinical trials comparing angioplasty and bypass surgery have been published. The trials excluded patients in whom survival had already been shown to be longer with bypass surgery than with medical therapy. Also, none of the trials was sufficiently large to detect relatively modest differences in survival between the 2 techniques. Most of the trials did not have a long-term follow-up, ie, 5 to 10 years, and therefore were unable to provide clear inferences regarding long-term benefit of the 2 techniques in similar populations. Also, and perhaps most notably, only ≈5% of screened patients with multivessel disease at enrolling institutions were included in the trials. Half of the patients approached were ineligible owing to left main coronary artery disease, insufficient symptoms, or other reasons. Even among a large group of patients with multivessel disease suitable for enrollment, only half were actually randomized. It appeared that physicians elected not to enroll many patients with 3-vessel disease in the trials but rather refer them for bypass surgery, whereas patients with 2-vessel disease tended to be referred for angioplasty rather than be enrolled in the trials.

Overall, procedural complications were low for both procedures but tended to be higher with CABG surgery (Table 6⇓). For patients randomized to angioplasty, CABG was needed in ≈6% during the index hospitalization and in nearly 20% by 1 year. The initial cost and length of stay were lower for angioplasty than for CABG. Patients having angioplasty returned to work sooner and were able to exercise more at 1 month. The extent of revascularization achieved by bypass surgery was generally higher than with angioplasty. Long-term survival was difficult to evaluate owing to the short period of follow-up and the small sample size of the trials. However, for the Bypass Angioplasty Revascularization Investigation (BARI) trial, bypass patients had a 5-year survival of 89.3% compared with 86.3% for angioplasty. Secondary analysis revealed that in treated diabetic patients in the BARI trials, CABG led to significantly superior survival compared with percutaneous transluminal coronary angioplasty (PTCA). However, this finding was not evident in other trials. In long-term follow-up, the most striking difference was the 4- to 10-fold-higher likelihood of reintervention after initial PTCA. Quality of life, physical activity, employment, and cost were similar by 3 to 5 years after both procedures. The BARI trial suggested higher mortality associated with PTCA in several high-risk groups, including those with diabetes, unstable angina, and/or non–Q wave MI, and in patients with heart failure.

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Table 6.

CABG vs PTCA: Randomized Controlled Trials

An analysis of registries generally shows data similar to those of the trials. However, a recent analysis of ≈60 000 patients who were treated in New York State in the early 1990s provides a 3-year survival analysis of patients undergoing CABG and PTCA. After adjustment for various covariates, bypass surgery in the New York State registry experience was associated with longer survival in patients with severe proximal LAD stenosis and/or 3-vessel disease. Contrariwise, patients with 1-vessel disease not involving the proximal LAD had improved survival with PTCA. Table 7⇓ summarizes survival data from the New York State registry with respect to various cohorts of patients undergoing angioplasty or bypass surgery. These data can be used to estimate 3-year survival expectations for patients with various anatomic features.

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Table 7.

Three-Year Survival by Treatment in Each Anatomic Subgroup

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V. Management Strategies

Reduction of Perioperative Mortality and Morbidity

1. Reducing the Risk of Type 1 Brain Injury After CABG

Postoperative neurological complications represent 1 of the most devastating consequences of CABG surgery. Type 1 injury, in which a significant, permanent, neurological injury is sustained, occurs in ≈3% of patients overall and is responsible for a 21% mortality.

Atherosclerotic Ascending Aorta

An important predictor of this complication is the surgeon’s identification of a severely atherosclerotic, ascending aorta before or during the bypass operation. Perioperative atheroembolism from aortic plaque is thought to be responsible for approximately one third of strokes after CABG. Atherosclerosis of the ascending aorta is strongly related to increased age. Thus, stroke risk is particularly increased in patients beyond 75 to 80 years of age. Preoperative, noninvasive testing to identify high-risk patients has variable accuracy. Computed tomography identifies the most severely involved aortas but underestimates mild or moderate involvement. Transesophageal echocardiography is useful for aortic arch examination, but examination of the ascending aorta may be limited by the intervening trachea. Intraoperative assessment with epiaortic imaging is superior to both methods. Intraoperative palpation underestimates the high-risk aorta. The highest-risk aortic pattern is a protruding or mobile aortic arch plaque. An aggressive approach to the management of patients with severely diseased ascending aortas identified by intraoperative echocardiographic imaging reduces the risk of postoperative stroke. For patients with aortic walls ≤3 mm thick, standard treatment is used. For aortas >3 mm thick, the cannulation, clamp, or proximal anastomotic sites may be changed, or a no-clamp, fibrillatory arrest strategy may be used. For high-risk patients with multiple or circumferential involvement or those with extensive middle ascending aortic involvement, replacement of the ascending aorta under hypothermic circulatory arrest may be indicated. Alternatively, a combined approach with off-bypass, in situ internal mammary grafting to the LAD and percutaneous coronary intervention to treat other vessel stenoses has conceptual merit.

Atrial Fibrillation and Stroke

Chronic atrial fibrillation is a hazard for perioperative stroke. Intraoperative surgical manipulation or spontaneous resumption of sinus rhythm during the early postoperative period may lead to embolism of a left atrial clot. One approach to reduce this risk is the performance of preoperative, transesophageal echocardiography. The absence of a left atrial clot would suggest that the operation may proceed with acceptable risk. For elective patients, if a left atrial clot is identified, 3 to 4 weeks of anticoagulation therapy followed by restudy and then subsequent surgery is reasonable. Few clinical trial data are available to assist clinicians in this circumstance.

New-onset postoperative atrial fibrillation occurs in ≈30% of post-CABG patients, particularly on the second and third postoperative days, and is associated with a 2- to 3-fold increased risk of postoperative stroke. Risk factors include advanced age, chronic obstructive pulmonary disease, proximal right coronary disease, prolonged operation, atrial ischemia, and withdrawal of β-blockers. The role of anticoagulants in patients who develop post-CABG atrial fibrillation is unclear. Aggressive anticoagulation and cardioversion may reduce the neurological complications associated with this arrhythmia. Early cardioversion within 24 hours of the onset of atrial fibrillation can probably be performed safely without anticoagulation. However, persistence of the arrhythmia beyond this time argues for the use of oral anticoagulants to reduce stroke risk in patients who remain in atrial fibrillation and/or in those for whom later cardioversion is planned.

Recent MI, LV Thrombus, and Stroke

Patients with a recent, anterior MI and residual wall-motion abnormality are at increased risk for the development of an LV mural thrombus and its potential for embolization. For patients undergoing surgical revascularization after sustaining an anterior MI, preoperative screening with echocardiography may be appropriate to identify the presence of a clot. Detection of an acute LV mural thrombus may call for long-term anticoagulation and reevaluation by echocardiography to ensure resolution or organization of the thrombus before coronary bypass surgery. Additionally, 3 to 6 months of anticoagulation therapy is appropriate for patients with persistent, anterior wall–motion abnormalities after coronary bypass surgery.

Recent, Antecedent Cerebrovascular Event

A recent, preoperative cerebrovascular accident represents a situation in which delaying surgery may reduce the perioperative neurological risk. In particular, evidence of a hemorrhagic component based on computed tomographic scan identifies high risk for the extension of neurological damage with cardiopulmonary bypass. It is generally believed that a delay of 4 weeks or more after a cerebrovascular accident is prudent, if coronary anatomy and symptoms permit, before proceeding with CABG.

Carotid Disease and Neurological Risk Reduction

Hemodynamically significant carotid stenoses are thought to be responsible for up to 30% of early postoperative strokes. The trend for coronary surgery to be performed in an increasingly elderly population and the increasing prevalence of carotid disease in this same group of patients underscore the importance of this issue. Perioperative stroke risk is thought to be <2% when carotid stenoses are <50%, 10% when stenoses are 50% to 80%, and 11% to 19% in patients with stenoses >80%. Patients with untreated, bilateral, high-grade stenoses and/or occlusions have a 20% chance of stroke. Carotid endarterectomy for patients with high-grade stenosis is generally done preceding or coincident with coronary bypass surgery and, with proper teamwork in high-volume centers, is associated with a low risk for both short- and long-term neurological sequelae. Carotid endarterectomy performed in this fashion carries a low mortality (3.5%) and reduces early postoperative stroke risk to <4%, with a concomitant 5-year freedom from stroke of 88% to 96%.

The decision about who should undergo preoperative carotid screening is controversial. Predictors of important carotid stenosis include advanced age, female sex, known peripheral vascular disease, previous transient ischemic attack or stroke, a history of smoking, and left main coronary artery disease. Many centers screen all patients >65 years old. Patients with left main coronary disease are often screened, as are those with a previous transient ischemic attack or stroke. Preoperative central nervous system symptoms suggestive of vertebral basilar insufficiency should lead to an evaluation before elective CABG.

When surgery of both carotid and coronary disease is planned, the most common approach is to perform the operation in a staged manner, in which the patient first has carotid surgery followed by coronary bypass in 1 to 5 days. Alternatively, especially if the patient has compelling cardiac symptoms or coronary anatomy, the operations may be performed during a single period of anesthesia, with the carotid endarterectomy immediately preceding coronary bypass. Neither strategy has been established as being superior. Stroke risk is increased if a reversed-stage procedure is used, in which the coronary bypass operation precedes the carotid endarterectomy by ≥1 day.

2. Reducing the Risk of Type 2 Brain Injury

Type 2 neurological complications are seen in ≈3% of patients and are correlated with a 10% risk of postoperative death, with 40% of patients requiring additional care in a transitional facility after hospital discharge. Microembolization is thought to be a major contributor to the postoperative cerebral dysfunction after CABG. The release of microemboli during extracorporeal circulation, involving small gaseous or lipid emboli, may be responsible. The use of a 40-μm arterial-line filter on the heart-lung machine circuit and routine use of membrane oxygenators rather than bubble oxygenators may reduce such neurological injury. Additional maneuvers to reduce type 2 neurological injury include the maintenance of steady, cerebral blood flow during cardiopulmonary bypass, avoidance of cerebral hyperthermia during and after cardiopulmonary bypass, meticulous control of perioperative hyperglycemia, and avoidance and limitation of postoperative cerebral edema.

3. Reducing the Risk of Perioperative Myocardial Dysfunction

Protection in Patients With Normal LV Function

There is no universally applicable myocardial protection technique. Among patients with preserved preoperative cardiac function, no strong argument can currently be made for warm versus cold and crystalloid versus blood cardioplegia. However, certain techniques may offer a wider margin of safety for special patient subsets.

Myocardial Protection for Acutely Depressed Cardiac Function

Several studies have suggested that blood cardioplegia (compared with crystalloid) may offer a greater margin of safety during CABG performed on patients with acute coronary occlusion, failed angioplasty, urgent revascularization for unstable angina, and/or chronically impaired LV function.

Protection for Chronically Depressed LV Function

The use of a prophylactic intra-aortic balloon pump as an adjunct to myocardial protection may reduce mortality in patients having CABG in the setting of severe LV dysfunction (eg, LVEF <0.25). Placement of the intra-aortic balloon pump immediately before operation appears to be as effective as placement on the day preceding bypass surgery.

Adjuncts to Myocardial Protection

Although it is widely appreciated that use of the internal mammary artery leads to improved long-term survival after coronary bypass surgery, it has also been documented that use of the internal mammary artery influences operative mortality itself. Thus, internal mammary artery use should be encouraged in the elderly, emergent, or acutely ischemic patient and other patient groups.

Inferior Infarct With Right Ventricular Involvement

An acutely infarcted right ventricle is at great risk for severe, postoperative dysfunction and predisposes the patient to a higher postoperative mortality. During operation, loss of the pericardial constraint may lead to acute dilatation of the dysfunctional right ventricle, which then fails to recover even with optimal myocardial protection and revascularization. The best defense against right ventricular dysfunction is its recognition during preoperative evaluation. When possible, CABG should be delayed for ≥4 weeks to allow the right ventricle to recover.

4. Reducing the Systemic Consequences of Cardiopulmonary Bypass

A variety of measures have been tried to reduce the systemic consequences of cardiopulmonary bypass, which elicits a diffuse inflammatory response that may cause transient or prolonged multisystem organ dysfunction. Administration of corticosteroids before cardiopulmonary bypass may reduce complement activation and release of proinflammatory cytokines. Proper timing and duration of corticosteroid application are incompletely resolved. The administration of the serine protease inhibitor aprotinin may attenuate complement activation and cytokine release during extracorporeal circulation. Unfortunately, aprotinin is relatively expensive. Another method to reduce the inflammatory response is perioperative leukocyte depletion through hematologic filtration.

5. Reducing the Risk of Perioperative Infections

Several methods exist to reduce the risk of wound infections in patients undergoing CABG. These begin with interval reporting to individual surgeons regarding their respective wound infection rates and adherence to sterile operative techniques. Additional strategies include skin preparation with topical antiseptics, clipping rather than shaving the skin, avoidance of hair removal, reduction of operating room traffic, laminar-flow ventilation, shorter operation, minimization of electrocautery, avoidance of bone wax, use of double-glove barrier techniques for the operating room team, and routine use of a pleural pericardial flap. Aggressive, perioperative glucose control in diabetics through the use of continuous, intravenous insulin infusion reduces perioperative hyperglycemia and its associated infection risk. Avoidance of homologous blood transfusions after CABG may reduce the risk of both viral and bacterial infections. This is due to an immunosuppressive effect of transfusion. Leukodepletion of transfused blood also reduces this effect. This can be accomplished by regional blood blanks at the time of donation or at the bedside by use of a transfusion filter.

Preoperative antibiotic administration reduces the risk of postoperative infection 5-fold. Efficacy is dependent on adequate drug tissue levels before microbial exposure. Cephalosporins are currently the agents of choice. Table 8⇓ identifies appropriate choices, doses, and routes of therapy. A 1-day course of intravenous antimicrobials is as effective as 48 hours or more. Therapy should be administered within 30 minutes of incision and again in the operating room if the operation exceeds 3 hours. Many centers deliver antibiotics just before incision. One fail-safe method is to have the anesthesiologist administer the cephalosporin after induction but before skin incision. If deep sternal wound infection does occur, aggressive surgical debridement and early vascularized muscle flap coverage are the most effective methods for treatment, along with long-term systemic antibiotics.

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Table 8.

Prophylactic Antimicrobials for Coronary Artery Bypass Graft Surgery

6. Prevention of Postoperative Dysrhythmias

Postoperative atrial fibrillation increases the length of stay, cost, and most important, the risk of stroke. Atrial fibrillation occurs in up to 30% of patients, usually on the second or third postoperative day. Methods to avoid atrial fibrillation are several. First, withdrawal of preoperative β-blockers in the postoperative period doubles the risk of atrial fibrillation after CABG. Thus, early reinitiation of β-blockers is critical for avoidance of this complication. Virtually every study of patients receiving β-blockers prophylactically has shown benefit in lowering the frequency of atrial fibrillation. Most have used the drug in the postoperative period, but greater benefit may occur if β-blockade is begun before the operation. More recently, small studies of propafenone, sotalol, and amiodarone have also shown effectiveness in reducing the risk of postoperative atrial fibrillation. Table 9⇓provides a review of pharmacological approaches in the randomized trials. Digoxin and calcium channel blockers have no consistent benefit for preventing atrial fibrillation after CABG, although they are frequently used to control its rate after it does occur. Currently, the routine preoperative or early postoperative administration of β-blockers is considered standard therapy to reduce the risk of atrial fibrillation after CABG.

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Table 9.

Pharmacological Strategies for Prevention of Atrial Fibrillation (AF) After Coronary Artery Bypass Graft Surgery

7. Strategies to Reduce Perioperative Bleeding and Transfusion Risk

Transfusion Risk

Despite the increasing safety of homologous blood transfusion, concerns surrounding viral transmission during transfusion remain. Currently, the risks are likely very low and have been estimated to be 1/493 000 for human immunodeficiency virus, 1/641 000 for human T-cell lymphotrophic virus, 1/103 000 for hepatitis C virus, and 1/63 000 for hepatitis B virus.

Perioperative Bleeding

Risk factors for blood transfusion after CABG include advanced age, low preoperative red blood cell volume, preoperative aspirin therapy, urgent operation, duration of cardiopulmonary bypass, recent thrombolytic therapy, reoperation, and differences in heparin management. Institutional protocols that establish minimum thresholds for transfusion lead to a reduced number of units transfused and the percentage of patients requiring blood. Additional strategies can reduce the transfusion requirement after CABG. For stable patients, aspirin and other antiplatelet drugs may be discontinued 7 days before elective CABG. Aprotinin, a serum protease inhibitor with antifibrinolytic activity, also decreases postoperative blood loss and transfusion requirements in high-risk patients. Although there has been some concern that aprotinin may reduce early graft patency, recent studies have failed to document this effect. Routine use of aprotinin is limited by its high cost. Multidisciplinary approaches to conserve blood in single institutions appear to be effective.

For patients without exclusions, such as low hemoglobin values, heart failure, unstable angina, left main coronary artery disease, or advanced anginal symptoms, self-donation of 1 to 3 units of red blood cells over 30 days before operation reduces the need for homologous transfusion during or after operation. Donation immediately before cardiopulmonary bypass yields a higher platelet and hemoglobin count compared with simple hemodilution without pre–cardiopulmonary bypass blood harvesting.

8. Antiplatelet Therapy for Saphenous Vein Graft Patency

Aspirin significantly reduces vein graft closure during the first postoperative year. The aspirin should be started within 24 hours after surgery because its benefit on saphenous vein graft patency is lost when begun later. Dosing regimens from as little as 100 mg/d to as much as 325 mg TID appear to be efficacious. Ticlopidine offers no advantage over aspirin but is an alternative in truly aspirin-allergic patients. Life-threatening neutropenia is a rare but recognized side effect. Clopidogrel offers the potential for fewer side effects compared with ticlopidine as an alternative in aspirin-allergic patients. Its incidence of severe leukopenia is rare.

9. Pharmacological Management of Hyperlipidemia

Aggressive treatment of hypercholesterolemia reduces progression of atherosclerotic vein graft disease in patients after bypass surgery. Statin therapy has been shown to reduce saphenous vein graft disease progression over the ensuing years after bypass. Patients with unknown low-density lipoprotein (LDL) cholesterol levels after bypass should have cholesterol levels determined and treated pharmacologically if the LDL exceeds 100 mg/dL. Patients with treated LDL cholesterol should have their low-fat diet and cholesterol-lowering medications continued after bypass surgery to reduce subsequent graft attrition. Data regarding the benefit of cholesterol lowering after bypass surgery are most supported by studies that have used HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, particularly targeting LDL levels to <100 mg/dL.

10. Hormonal Manipulation

While observational studies have suggested that hormone replacement therapy in postmenopausal women leads to a reduction in all-cause mortality, a recent, randomized trial for secondary coronary prevention failed to show a beneficial effect on the overall rate of coronary events. Thus, hormone replacement therapy should be considered in postmenopausal women after bypass when, in the physician’s judgment, the potential coronary benefit is not offset by an increased risk of uterine or breast cancer.

11. Smoking Cessation

Smoking cessation is the single, most important risk-modification goal after CABG in patients who smoke. Smoking cessation leads to less recurrent angina, improved physical function, fewer admissions, maintenance of employment, and improved survival. Treatment individualized to the patient is crucial. Depression may be an important complicating factor and should be approached with behavioral and drug therapy. Nicotine replacement with a transdermal patch, nasal spray, gum, or inhaler is beneficial. A sustained-release form of bupropion, an antidepressant similar to selective serotonin reuptake inhibitors, reduces the nicotine craving and anxiety of smokers who quit. All smokers should receive educational counseling and be offered smoking cessation therapy after CABG (Table 10⇓).

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Table 10.

Proven Management Strategies to Reduce Perioperative and Late Morbidity and Mortality

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Table 1.

12. Cardiac Rehabilitation

Cardiac rehabilitation, including early ambulation during hospitalization, outpatient prescriptive exercise, family education, and dietary and sexual counseling, has been shown to improve outcomes after CABG. The benefits include better physical mobility and perceived health. A higher proportion of rehabilitated patients are working at 3 years after CABG. The benefits of rehabilitation extend to the elderly and to women. Cardiac rehabilitation reinforces pharmacological therapy and smoking cessation and should be offered to all eligible patients after CABG.

13. Emotional Dysfunction and Psychosocial Considerations

Lack of social participation and low religious strength are independent predictors of death in elderly patients undergoing CABG. Although controversial, the high prevalence of depression after bypass surgery may reflect a high prevalence preoperatively. Cardiac rehabilitation has a highly beneficial effect in patients who are moderately or severely depressed. Evaluation of social supports and attempts to identify and treat underlying depression should be part of routine post-CABG care.

14. Rapid Sustained Recovery After Operation

Rapid recovery and early discharge are standard goals after CABG. The shortest in-hospital postoperative stays are followed by the fewest rehospitalizations. Important components of “fast-track” care are careful patient selection, patient and family education, early extubation, prophylactic antiarrhythmic therapy, dietary considerations, early ambulation, early outpatient telephone follow-up, and careful coordination with other physicians and healthcare providers.

15. Communication Between Caregivers

Maintenance of appropriate and timely communication between treating physicians regarding care of the patient is crucial. When possible, the primary care physician should follow up the patient during the perioperative course. The referral physician needs to provide clear, written reports of the findings and recommendations to the primary care physician, including discharge medications and dosages along with long-term goals.

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VI. Impact of Evolving Technology

A. Less-Invasive Coronary Bypass Surgery

Technical modifications of CABG have been developed to decrease the morbidity of the operation, either by using limited incision or by eliminating cardiopulmonary bypass. Currently, “less-invasive” CABG surgery can be divided into 3 categories: (1) off-bypass CABG performed through a median sternotomy with a smaller skin incision, (2) minimally invasive direct CABG (MID-CAB) performed through a left anterior thoracotomy without cardiopulmonary bypass, and (3) port-access CABG with femoral-to-femoral cardiopulmonary bypass and cardioplegic arrest with limited incision.

Off-bypass coronary surgery is performed on a beating heart after reduction of cardiac motion with a variety of pharmacological and mechanical devices. These include slowing the heart with β-blockers and calcium channel blockers and use of a mechanical stabilizing device to isolate and stabilize the target vessel. Retraction techniques may elevate the heart to allow access to vessels on the lateral and inferior surfaces of the heart. Because this technique generally uses a median sternotomy, its primary benefit is the avoidance of cardiopulmonary bypass, not a less extensive incision.

MID-CAB refers to bypass surgery without median sternotomy and without the use of cardiopulmonary bypass. Generally, this is performed with a small left anterior thoracotomy, exposing the heart through the fourth intercostal interspace with access to the LAD and diagonal branches and occasionally, the anterior marginal vessels. The right coronary artery can be approached by using a right anterior thoracotomy. MID-CAB procedures are generally performed on only 1 or 2 coronary targets. Observational studies have suggested that MID-CAB is associated with a reduced average length of stay and an earlier return to work. Although initial reports of 2-year actuarial and event-free survival are encouraging, the data must be viewed with caution. Because the number of anastomoses performed on a beating heart is usually 1 or occasionally 2, the potential long-term effects of incomplete revascularization are unknown.

The closed-chest, port-access, video-assisted CABG operation uses cardiopulmonary bypass and cardioplegia of a globally arrested heart. Vascular access for cardiopulmonary bypass is achieved via the femoral artery and vein. A triple-lumen catheter with an inflatable balloon at its distal end is used to achieve endovascular aortic occlusion, cardioplegia delivery, and LV decompression. With cardiopulmonary bypass and cardioplegic arrest, CABG can be performed with video assistance on a still and decompressed heart through several small ports. In comparison with the MID-CAB, port access allows access to different areas of the heart, thus facilitating more complete revascularization, and the motionless heart may allow a more accurate anastomosis. Compared with conventional CABG, median sternotomy is avoided. However, potential morbidity of the port-access operation includes multiple wounds at port sites, the limited thoracotomy, and the groin dissection for femoral-femoral bypass. Vigorous scrutiny of the long-term benefits versus risks of port access is required.

B. Arterial and Alternate Conduits

Another area of evolving technology is the use of arterial and alternate conduits. The 5-year patency of coronary artery–vein bypass grafts is 74%, and at 10 years, just 41%. Contrariwise, patency rates of the internal mammary artery implanted into the LAD are as high as 83% at 10 years. As a consequence of improved patency, patients receiving an LAD graft with an internal mammary artery have improved survival compared with patients receiving only vein grafts. Currently, routine use of the left internal mammary artery for LAD grafting with supplemental saphenous vein grafts to other coronary lesions is generally accepted as a standard grafting method. The use of bilateral internal mammary arteries appears to be safe and efficacious. However, there is a higher rate of deep sternal wound infection when both internal mammary arteries are used. This is particularly true for patients with obesity and diabetes and perhaps for those requiring prolonged ventilatory support. The benefits of bilateral internal mammary artery use include lower rates of recurrent angina, MI, and need for reoperation and a trend for better survival. Recently, the radial artery has been used more frequently as a conduit for coronary bypass surgery. Five-year patency appears to be in the range of 85% (compared with nearly 90% for the internal mammary graft). In patients for whom mammary artery, radial artery, and standard vein conduits are unavailable, the in situ right gastroepiploic artery, the inferior epigastric free artery graft, and either lesser saphenous or upper-extremity vein conduits have been used. Long-term patency of these alternative grafts has not been extensively studied.

C. Percutaneous Technology

Technological improvements in percutaneous coronary angioplasty have included the introduction of new devices and improved medical therapy of patients in whom angioplasty is performed. The most notable improvement has been the introduction of intracoronary stents that have reduced late restenosis and the frequency with which emergency bypass surgery is required after PTCA. Intracoronary stents have been used to treat saphenous vein graft stenosis in patients with previous CABG. However, stented patients still have an ≈25% combined rate of death, MI, need for repeat CABG, or re-revascularization of the target vessel. For some patients, hybrid procedures may be the best choice, such as the combined use of CABG surgery and coronary angioplasty. Such an approach is relevant to the patient whose ascending aorta is involved with severe atherosclerosis, for which the implantation of free vein grafts or arterial grafts leads to risk for atheroembolism. In such a patient, the use of in situ internal mammary artery grafting without cardiopulmonary bypass combined with additional coronary angioplasty in other diseased vessels represents a strategy to provide complete revascularization without the concomitant risks of cardiopulmonary bypass and/or manipulation of the ascending aorta.

D. Transmyocardial Revascularization

A fourth area that is rapidly evolving is transmyocardial revascularization. The use of transmyocardial laser revascularization has generally been performed surgically for patients with severe angina refractory to medical therapy and who are not suitable candidates for standard surgical revascularization, PTCA, or heart transplant. While several studies have suggested improvement in angina severity with transmyocardial laser revascularization, the mechanism by which angina improves and the overall benefit on long-term angina and/or survival await further clarification.

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VII. Special Patient Subsets

A. Elderly Patients

Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.

B. Women

A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.

C. Diabetic Patients

Coronary heart disease is the leading cause of death among adult diabetics and accounts for 3 times as many deaths among diabetics as among nondiabetics. While CABG carries an increased morbidity and mortality in diabetics, data suggest that in appropriate candidates, the absolute risk reduction provided by successful revascularization remains high. The BARI trial suggested that diabetics with multivessel coronary disease derived advantage from bypass surgery compared with angioplasty. Several of the other randomized trials, albeit with smaller numbers of patients, failed to show this trend. Diabetics who are candidates for renal transplantation have a particularly high incidence of coronary artery disease, even in the absence of symptoms or signs. In appropriate candidates, CABG appears to offer morbidity and mortality benefit in such patients.

D. Patients With Chronic Obstructive Pulmonary Disease

Because CABG is associated with variable degrees of postoperative respiratory insufficiency, it is important to identify patients at particular risk for pulmonary complications. The intent is to treat reversible problems that may contribute to respiratory insufficiency in high-risk patients, with the hope of avoiding prolonged periods of mechanical ventilation after CABG. High-risk patients often benefit from preoperative antibiotics, bronchodilator therapy, a period of cessation from smoking, perioperative incentive spirometry, deep-breathing exercises, and chest physiotherapy. If pulmonary venous congestion or pleural effusions are identified, diuresis often improves lung performance.

Although preoperative spirometry directed to identifying patients with a low (eg, <1 L) 1-second forced expiratory volume has been used by some to qualify or disqualify candidates for CABG, clinical evaluation of lung function is likely as important if not more so. Patients with advanced chronic obstructive pulmonary disease are at particular risk for postoperative arrhythmias that may be fatal. While moderate to severe degrees of obstructive pulmonary disease represent a significant risk factor for early mortality and morbidity after CABG, it is also true that with careful preoperative assessment and treatment of the underlying pulmonary abnormality, many such patients are successfully carried through the operative procedure.

E. Patients With End-Stage Renal Disease

Coronary artery disease is the most important cause of mortality in patients with end-stage renal disease. Many of such patients have diabetes and other coronary risk factors, including hypertension, myocardial dysfunction, abnormal lipids, anemia, and increased plasma homocysteine levels. Although patients on chronic dialysis are at higher risk when undergoing coronary angioplasty or bypass, they are at even higher risk with conservative medical management. Thus, in patients with modest reductions in LV function, significant left main or 3-vessel disease, and/or unstable angina, coronary revascularization can lead to relief of coronary symptoms, improvement in overall functional status, and improved long-term survival in this select high-risk patient population.

F. Reoperative Patients

Operative survival and long-term benefit of reoperative CABG are distinctly inferior to first-time operations. Patients undergoing repeated CABG have higher rates of postoperative bleeding, perioperative MI, and neurological and pulmonary complications. Nevertheless, reasonable 5- and 10-year survival rates after reoperation for coronary disease can be achieved, and the operation is appropriate if the severity of symptoms and anticipated benefit justify the immediate risk. Data suggest that the need for reoperation is less common in patients undergoing internal mammary artery grafting to the LAD. More recently, short-term follow-up studies suggest that patients undergoing multiple arterial grafts have even lower rates of reoperation. These early results are consistent with the known superior graft patency of arterial conduits compared with vein grafts.

G. Concomitant Peripheral Vascular Disease

The presence of clinical and subclinical peripheral vascular disease is a strong predictor of increased hospital and long-term mortality rates in patients undergoing CABG. However, the absolute benefit offered by coronary revascularization is elevated in patients with peripheral vascular disease, particularly those with 3-vessel coronary disease, more advanced angina, and/or a depressed LVEF. Excess perioperative mortality in such patients is related to an increased incidence of heart failure and dysrhythmias rather than peripheral arterial complications.

H. Poor LV Function

Patients with severe LV dysfunction have increased perioperative and long-term mortality compared with patients with normal LV function. However, studies suggest that the beneficial effects of myocardial revascularization in patients with ischemic heart disease and severe LV dysfunction are sizeable when compared with medically treated patients of similar status in terms of symptom relief, exercise tolerance, and survival.

I. CABG in Acute Coronary Syndromes

Coronary bypass surgery offers a survival advantage compared with medical therapy in patients with unstable angina and LV dysfunction, particularly in the presence of 3-vessel disease. However, the risk of bypass surgery in patients with unstable or postinfarction angina or early after non–Q wave infarction and during acute MI is increased severalfold compared with patients with stable angina. Although this risk is not necessarily higher than that with medical therapy, it has led to the argument to consider angioplasty or to delay CABG in such patients if medical stabilization can be easily accomplished.

Previous SectionNext Section

VIII. Institutional and Operator Competence

Studies suggest that mortality after CABG is higher when carried out in institutions that annually perform fewer than a minimum number of cases. Similar conclusions have been drawn regarding individual surgeons’ volumes. This observation strengthens the argument for careful outcome tracking and supports the monitoring of institutions or individuals who annually perform <100 cases. It is also true that there is a wide variation in risk-adjusted mortality rates in low-volume situations. Thus, some institutions and practitioners maintain excellent outcomes despite relatively low volumes.

Outcome reporting in the form of risk-adjusted mortality rates after bypass has been effective in reducing mortality rates nationwide. Public release of hospital and physician-specific mortality rates has not been shown to drive this improvement and has failed to effectively guide consumers or alter physician referral patterns.

Previous SectionNext Section

IX. Cost-Effectiveness of Bypass Surgery

A variety of studies of CABG have found the technique to be cost-effective in patients for whom survival and/or symptomatic benefit is demonstrable. Within these subsets, the cost-effectiveness of CABG compares favorably with that of other accepted medical therapies.

When compared with PTCA, the initial hospital cost of CABG is significantly higher. However, by 5 years, the cumulative cost of PTCA compared with initial surgical therapy is within 5% of CABG, or a difference of <$3000. Observational studies showing a poorer survival effect of PTCA in patients with more advanced disease suggest that there may be a significant cost gradient for PTCA as the extent of disease increases, which is not apparent for coronary bypass surgery.

Previous SectionNext Section

X. Indications

A. Indications for CABG in Asymptomatic or Mild Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater in patients with abnormal LV function; eg, with an EF <0.50.)

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*¹

Class IIb

1. One- or 2-vessel disease not involving the proximal LAD.†²

Class III

See text.

B. Indications for CABG in Stable Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater when LVEF is <0.50.)

4. Two-vessel disease with significant proximal LAD stenosis and either EF <0.50 or demonstrable ischemia on noninvasive testing.

5. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a large area of viable myocardium and high-risk criteria on noninvasive testing.

6. Disabling angina despite maximal medical therapy, when surgery can be performed with acceptable risk. If angina is not typical, objective evidence of ischemia should be obtained.

Class IIa

1. Proximal LAD stenosis with 1-vessel disease.*¹

2. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing.

Class III

1. One- or 2-vessel disease not involving significant proximal LAD stenosis, in patients (1) who have mild symptoms that are unlikely due to myocardial ischemia or have not received an adequate trial of medical therapy and (A) have only a small area of viable myocardium or (B) have no demonstrable ischemia on noninvasive testing.

2. Borderline coronary stenoses (50% to 60% diameter in locations other than the left main coronary artery) and no demonstrable ischemia on noninvasive testing.

3. Insignificant (<50% diameter) coronary stenosis.

C. Indications for CABG in Unstable Angina/Non–Q Wave MI

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Ongoing ischemia not responsive to maximal nonsurgical therapy.

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*¹

Class IIb

2. One- or 2-vessel disease not involving the proximal LAD.†²

Class III

See text.

D. Indications for CABG in ST-Segment Elevation (Q-Wave) MI

Class I

None.

Class IIa

1. Ongoing ischemia/infarction not responsive to maximal nonsurgical therapy.

Class IIb

1. Progressive LV pump failure with coronary stenosis compromising viable myocardium outside the initial infarct area.

2. Primary reperfusion in the early hours (≤6 to 12 hours) of an evolving ST-segment elevation MI.

Class III

1. Primary reperfusion late (≥12 hours) in evolving ST-segment elevation MI without ongoing ischemia.

E. Indications for CABG in Poor LV Function

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Proximal LAD stenosis with 2- or 3-vessel disease.

Class IIa

1. Poor LV function with significant viable, noncontracting, revascularizable myocardium without any of the aforementioned anatomic patterns.

Class III

1. Poor LV function without evidence of intermittent ischemia and without evidence of significant revascularizable, viable myocardium.

F. Indications for CABG in Life-Threatening Ventricular Arrhythmias

Class I

1. Left main coronary artery stenosis.

2. Three-vessel coronary disease.

Class IIa

1. Bypassable 1- or 2-vessel disease causing life-threatening ventricular arrhythmias.‡³

2. Proximal LAD disease with 1- or 2-vessel disease.‡³

Class III

1. Ventricular tachycardia with scar and no evidence of ischemia.

G. Indications for CABG After Failed PTCA

Class I

1. Ongoing ischemia or threatened occlusion with significant myocardium at risk.

2. Hemodynamic compromise.

Class IIa

1. Foreign body in crucial anatomic position.

2. Hemodynamic compromise in patients with impairment of coagulation system and without previous sternotomy.

Class IIb

1. Hemodynamic compromise in patients with impairment of coagulation system and with previous sternotomy.

Class III

1. Absence of ischemia.

2. Inability to revascularize owing to target anatomy or no-reflow state.

H. Indications for CABG in Patients With Previous CABG

Class I

1. Disabling angina despite maximal noninvasive therapy. (If angina is not typical, then objective evidence of ischemia should be obtained.)

Class IIa

1. Bypassable distal vessel(s) with a large area of threatened myocardium on noninvasive studies.

Class IIb

1. Ischemia in the non-LAD distribution with a patent internal mammary graft to the LAD supplying functioning myocardium and without an aggressive attempt at medical management and/or percutaneous revascularization.

Class III

See text.

Previous Section

Footnotes

• “ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)” was approved by the American College of Cardiology Board of Trustees in March 1999 and by the American Heart Association Science Advisory and Coordinating Committee in July 1999.

• When citing this document, the American College of Cardiology and the American Heart Association request that the following citation format be used: Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J, Gardner TJ, Gott JP, Herrmann HC, Marlow RA, Nugent W, O’Connor GT, Orszulak TA, Rieselbach RE, Winters WL, Yusuf S. ACC/AHA guidelines for coronary artery bypass graft surgery: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 1999;100:1464-1480.

• This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). A single reprint of the executive summary and recommendations is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0173. To obtain a reprint of the complete guidelines published in the October 1999 issue of the Journal of the American College of Cardiology, ask for reprint No. 71-0174. To purchase additional reprints (specify version and reprint number): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or . To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.

• ↵1 Becomes Class I if extensive ischemia documented by noninvasive study and/or an LVEF <0.50.

• ↵2 If a large area of viable myocardium and high-risk criteria on noninvasive testing, becomes Class I.

• ↵3 Becomes Class I if arrhythmia is resuscitated sudden cardiac death or sustained ventricular tachycardia.

• CPB indicates cardiopulmonary bypass.

• Data taken from (1) Townsend TR, Reitz BA, Bilker WB, Bartlett JG. Clinical trial of cefamandole, cefazolin, and cefuroxime for antibiotic prophylaxis in cardiac operations. J Thorac Cardiovasc Surg. 1993;106:664–670. (2) Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther. 1997;39:97–101. (3) Vuorisalo S, Pokela R, Syrjala H. Comparison of vancomycin and cefuroxime for infection prophylaxis in coronary artery bypass surgery. Infect Control Hosp Epidemiol. 1998;19:234–239. (4) Romanelli VA, Howie MB, Myerowitz PD, Zvara DA, Rezaei A, Jackman DL, Sinclair DS, McSweeny TD. Intraoperative and postoperative effects of vancomycin administration in cardiac surgery patients: a prospective, double-blind, randomized trial. Crit Care Med. 1993;21:1124–1131.

• Copyright © 1999 by American Heart Association

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SOURCE

http://circ.ahajournals.org/content/100/13/1464.long

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