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Sample Accomplishments of VA Research with Dogs: 1960-Current Decade

What has VA research with dogs accomplished?

Which VA Station was Responsible for this Research?

When was the work done?

Pre-1980

1980s

1990s

2000s

2010-present

1. A cardiac pacemaker that could be implanted and counted on to work for many years was developed through VA research with dogs. More than 60,000 Veterans now have implanted pacemakers improving their quality of life.

Buffalo

X

2. “The Father of Transplantation” was a VA surgeon and researcher whose research with dogs made it possible to replace failing organs –including kidney, liver, heart, and lungs – with healthy ones.

Denver

X

3. VA research with dogs established the link between smoking and lung cancer. This was reported by the New York Times to have saved 750,000 lives by 1989

East Orange

X

4. Contributed to the development of endoscopic methods to control bleeding from peptic ulcers, which are 2-3 times more likely in Veterans with PTSD than in the general population. Endoscopy is far safer than the surgical approaches available previously.

Los Angeles

X

X

X

5. VA research with dogs has added to what is known about how medicines needed for anesthesia and pain relief also depress parts of the brain that manage respiration. Designing ways to prevent respiratory depression while effectively controlling pain depends on this knowledge.

Milwaukee

X

X

X

X

6. VA research with dogs was the basis for the development of a wearable artificial pancreas for people with diabetes. Nearly one in four Veterans receiving care in the VA has diabetes and stands to benefit as this technology continues to develop, improving the control of blood sugar levels without repeated insulin shots.

Los Angeles

X

X

X

X

7. VA research in dogs showed that drugs like Ciprofloxacin (“Cipro”) can safely get to and act on bacteria in tissues of the urinary tract. This justified trying them for treating bacterial prostatitis or other urinary tract infections (UTIs) in human subjects. The new treatment options that these led to were especially important to Veterans with spinal cord injuries because of their increased risk of UTIs – one study found that 40% of them had had UTIs over 13 years.

Madison

X

8. Insulin was discovered through research with dogs in Canada in the early 1900s, changing diabetes from a death sentence to a manageable disease. Some 5.7 million Veterans (almost 1 in 4) have diabetes. VA research continued efforts to understand how insulin secretion by the pancreas is controlled.

Louisville and Houston

X

X

9. VA research with dogs added to understanding of why the heart may fail to pump properly and how it can be helped by Beta blockers and ACE inhibitors. In 2010 alone, the VA treated 117,870 Veterans with heart failure.

Charleston

X

X

X

10. VA research with dogs identified the specific changes in specific places in the brain that cause narcolepsy. The opposite brain changes have now been observed with exposure to opioids. This means that continuing research to find better ways to treat people with narcolepsy is now likely to be valuable to understanding and treating opioid use disorder as well.

Los Angeles

X

X

X

X

11. VA research with dogs characterized the contractions of the gastrointestinal system and how they are changed by antibiotics, immunosuppressive drugs, and radiation therapy that have GI side effects, so that strategies to limit those side effects could be developed.

Milwaukee

X

X

X

X

12. VA research with dogs validated the use of ultrasound to measure kidney blood flow, making it much easier to identify the Veterans who can benefit from new treatment options for preserving kidney function and controlling hypertension.

Albuquerque

X

13. Research with dogs made it possible for Veterans with spinal cord injuries to breathe without a ventilator and to cough effectively, dramatically reducing hospitalizations for potentially lethal pneumonia and improving their quality of life. VA research has now developed an improved approach to cough stimulation that can be used in people for whom the existing system would be intolerably painful.

Cleveland

*

*

X

14. Improved techniques for surgery to correct problems that develop after hip replacement. This is necessary in about 10% of people who have hip replacements, or almost 17,000 Veterans.

Madison

X

15. Diabetes, which affects almost 1 in 4 Veterans, is the result when the blood sugar levels are not adequately controlled. Those levels are adjusted by hormones secreted by the pancreas, and there are nerves that act on the pancreas to adjust its secretions. VA research with dogs increased understanding of what those nerves do.

Seattle

X

16. Developed some of the key instruments and techniques for ablation, a way to cure disturbances of heart rhythm that some 400,000 Veterans have, by selectively destroying abnormal heart tissue. This is now used routinely in the cardiac clinic.

Oklahoma City

X

X

17. Developed bioengineered vascular scaffolds to improve blood flow for transplanted tissue and grafts.

Hines

X

X

18. In people and dogs, once melanoma spreads to distant sites it is usually incurable. VA research with dogs has led to vaccines for both dogs and humans, against this deadly cancer.

Madison

*

*

*X

19. Identified the genetic basis for an immune deficiency disorder, leukocyte adhesion deficiency. This was the basis for the development of gene therapy to treat this disorder.

Seattle

X

*

*

20. Developed and optimized electrode arrays for stimulating peripheral nerves to enhance bladder control for use in patients with spinal cord injury.

Hines

X

21. Developed a way to repair damaged intervertebral discs, which are responsible for back pain experienced by roughly 13,000 Veterans each year, often related to their service-related repetitive heavy load bearing and carrying.

Atlanta

X

22. Advanced the technology for stimulating breathing muscles in Veterans with spinal cord injuries by improving electrical leads and methods of stimulating the breathing muscles.

Hines

X

X

23. Increased understanding of why the heart’s beating can get out of control, beating at rates over 200 beats/min, and even becoming completely uncoordinated, and then what can be done to bring it back under control.

Iowa City

X

X

24. Contributed to the development of techniques for applying mild electrical stimulation to the intestinal tract to control obesity, a problem for as many as 8 million Veterans, and to improve bowel function after spinal cord injury.

Oklahoma City

X

X

25. Improved understanding of how conditions that the heart is exposed to increase the risks of atrial fibrillation, a common complication after heart surgery.

St. Louis

X

X

26. Increased understanding of how to protect vision that is threatened by glaucoma, which has been diagnosed in some 1.5 million Veterans, and is a leading cause of blindness worldwide.

Iowa City

X

27. Showed that disturbances of heart rhythms can interfere with heart function, not just because of the rhythm but because of effects on how the heart muscle works.

Richmond

X

28. Uncovered cellular mechanisms involved in the impairment of heart function induced by Premature Ventricular Contractions.

Richmond

X

29. Uncovered how Premature Ventricular Contractions disrupt the balance of the autonomic nervous system, which triggers more cardiac arrhythmias.

Richmond

X

30. Demonstrated that postoperative Atrial Fibrillation can be safely and effectively prevented by delivering agents packaged in slow- release nanoparticles, to suppress the activity of cardiac nerves on the surface of the atria.

Richmond

X

*Research conducted in these decades by the same researchers, but not while supported by VA.

Samples of How VA Research Has Helped Veterans

Project 1.

Headline: Development of a long-lasting implantable cardiac pacemaker

Bottom Line: A cardiac pacemaker that could be implanted and counted on to work for many years was developed through VA research with dogs. More than 60,000 Veterans now have implanted pacemakers improving their quality of life.

What Veterans face: When the heart’s rhythm becomes irregular, or the heart doesn’t keep up with beating at the rate that is needed to pump blood around the body, it becomes harder and harder for the person to do anything physical. The person may feel dizzy, faint, become short of breath, and have to rely on a wheelchair to get around. Before pacemakers became available, many lives were dramatically shortened because of such problems.

What VA research did, and when:

Today, almost everyone has a friend or family member with an implanted cardiac pacemaker, and pacemakers are common enough for the instructions for airport security procedures to mention them. Many researchers around the world were involved in finding ways to support effective heart rhythms when the heart can no longer manage to control them itself, but a crucial contribution was the work done with dogs at the VA in the 1950s-1960s to develop a long-lasting device that could be fully implanted. The size of the canine heart, and the similarities of its electrophysiological properties to those in human hearts (unlike those in other species of animals), made it possible for this research with dogs to work out important features of the pacemaker design before it was tried in human subjects.

VA involvement: The researchers who conducted this work included William Chardack and Andrew Gage, who held appointments at the Buffalo VA Medical Center, in Buffalo, NY, and conducted their research there. Dr. Chardack was the Chief of Surgery at the Buffalo VAMC.

Reference:  William M. Chardack, MD, Andrew A. Gage, MD, Wilson Greatbatch, MS. A Transistorized, Self-Contained, Implantable Pacemaker For The Long-Term Correction of Complete Heart Block Surgery Vol. 48 No. 4, Oct. 1960

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Project 2.

Headline: Pioneering research that made solid organ transplantation possible

Bottom Line: “The Father of Transplantation” was a VA surgeon and researcher whose research with dogs made it possible to replace failing organs – including kidney, liver, heart, and lungs – with healthy ones.

What Veterans face: Some 60,000 Veterans are treated for chronic liver failure each year. These Veterans have to deal with serious degradation of their quality of life, beginning with nausea, loss of appetite, fatigue, and diarrhea, progressing to problems with blood clotting, digestion, swelling, mental confusion, extreme sleepiness, coma, and death. It can be caused by diseases like hepatitis or cancer, by autoimmune disorders, by genetic disorders, by malnutrition, and by excess exposure to certain drugs or alcohol. Liver transplantation is the only way to restore liver function to a person with chronic liver failure.

What VA research did, and when: To successfully transplant organs like the liver, doctors needed to know how to face a number of tough challenges: how to keep donor organs healthy after they were removed from the donor until they were in place in the recipient, how to prevent blood clots from forming while blood flow was interrupted during surgery, what surgical techniques to use to restore proper blood flow through the transplanted organ, and how to prevent the immune system from attacking the transplanted organ. Several years of VA research with dogs, beginning in the late 1950s, were central to making it reasonable to attempt liver transplantation in human patients in the early 1960s. VA continued to support the research, including more research with dogs, to refine and improve the procedures, until liver transplantation became an established medical procedure in the late 1970s. The principles worked out in dogs for liver transplantation turned out to be key to successful transplantation of other organs as well, making it possible for hundreds of thousands of people in the US, including Veterans, to get a second chance at life over the past 30 years. In 2016 alone, these included some 20,000 kidney transplants, 7841 liver transplants, 3209 heart transplants, 2345 lung transplants, and 147 intestine transplants.

VA involvement: The researchers who conducted this work included Thomas E Starzl, who held appointments and conducted his research at the Rocky Mountain Regional VA Medical Center in Aurora, CO, and later at the VA Pittsburgh Healthcare System in Pittsburgh, PA.

Reference: Thomas E. Starzl, MD, F.A.C.S., Thomas L. Marchioro, MD, William R. Waddell, MD, F.A.C.S. The Reversal of Rejection in Human Renal Homografts With Subsequesnt Development of Homograft Tolerance Surgery, Gynecology & Obstentrics, Oct. 1963 Vol. 117, 385-395

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Project 3.

Headline: Smoking increases the risks of lung cancer

Bottom Line: VA research with dogs established the link between smoking and lung cancer. This was reported by the New York Times to have saved 750,000 lives by 1989.

What Veterans face: The incidence of lung cancer is higher, and the survival is lower, in Veterans than in non-Veterans. It is now recognized that this is related to the exposure of active duty military personnel to Agent Orange, radon, asbestos, beryllium, chromium, diesel exhaust, pesticides, pollutants and particulate matter from burn pits, oil well fires, destruction of chemical weapons, as well as to the larger proportion of Veterans than non-Veterans who smoke.

What VA research did, and when: Pioneering work at the East Orange VAMC in the 1960s established the causal link between active smoking and lung cancer. Earlier observations linked lung disorders and cigarette smoke, but were criticized by the tobacco industry as failing to demonstrate that the cigarette smoke induced the lung cancer. The VA research with dogs was the basis for the warning labels on cigarette packages, over the continued vigorous objections and unfounded criticisms of the Tobacco Institute. By 1989, the New York Times reported estimates that 750,000 lives had been saved by the warnings (which would correspond proportionally to about 47,000 Veterans)

VA involvement: The researchers who conducted this work included Oscar Auerbach and David Kirman, who held appointments and conducted their research at the Veterans Affairs Medical Center in East Orange, NJ.

Reference: Ford Burkhart. Oscar Auerbach, 92, Dies; Linked Smoking to Cancer. New York Times. Jan. 16, 1997

Oscar Auerbach, MD, E. Cuyler Hammond, ScD, David Kirman, Lawrence Garfinkel, MA. Emphysema Produces in Dogs by Cigarette Smoking JAMA, Jan. 23, 1967. Vol. 199, No 4.

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Project 4.

Headline: Treatment of bleeding ulcers without surgery

Bottom Line: Contributed to the development of endoscopic methods to control bleeding from peptic ulcers, which are 2-3 times more likely in Veterans with PTSD than in the general population.

Endoscopy is far safer than the surgical approaches available previously.

What Veterans face: Veterans with PTSD are estimated to be at 2-3 times higher risk of getting peptic ulcers than are people without PTSD. The ulcers bleed in about a tenth of those with peptic ulcers, which means that over 5000 Veterans per year may need treatment to stop the bleeding. Uncontrolled, the bleeding can lead to anemia and even death.

What VA research did, and when: Surgical treatment of severe bleeding ulcers carries the risks of surgical complications, but was the only option available before safe and effective endoscopic

approaches were developed. Endoscopy involves passing a flexible tube through the person’s mouth, into the esophagus, stomach, and small intestine. A light and a camera, to let the doctor see inside those organs, and instruments for treating the bleeding, are passed down the tube to reach the ulcer. Carefully controlled VA research with dogs starting in the 1980s and continuing into the 2000s, contributed to developing this method, which has become the improved standard clinical treatment for human patients.

VA involvement: The researchers who conducted this work included Dennis Jensen and GA Machicado, who held appointments and conducted their research at the VA Greater Los Angeles Healthcare System in Los Angeles, CA.

Reference: Jensen DM, Machicado GA. Hemoclipping of chronic canine ulcers: a randomized, prospective study of initial deployment success, clip retention rates, and ulcer healing. Gastrointest Endosc. 2009;70:969–975. [PMC free article] [PubMed]

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Project 5.

Headline: Pain relief without respiratory arrest

Bottom Line: VA research with dogs has added to what is known about how medicines needed for anesthesia and pain relief also depress parts of the brain that manage respiration. Designing ways to prevent respiratory depression while effectively controlling pain depends on this knowledge

What Veterans face: Veterans face many conditions that require surgical anesthesia or long-term pain management. These include spinal cord injuries and other traumatic injuries, cancers, and organ failure that requires transplantation. The medications involved, and the opioid use disorders that can develop, can slow breathing to the point of causing unconsciousness, brain damage, and even death. What VA research did, and when: Beginning in the 1980s, VA research with dogs has zeroed in on specific groups of cells in the brain that appear to be responsible for the effects of opioids on breathing. On-going work is to figure out how opioids act on these cells, how sedatives influence the effects of the opioids, and how these cells interact with cells in other parts of the brain, to adjust breathing to meet demands. This work can’t be done with computer models, because the information needed to build such models is the information that the research is focused on figuring out. The work depends on hours of meticulous study of individual brain cells in dogs, because the brain regions and cells in smaller animals are too small and close together, so that the needed observations are impossible to make in smaller animals. Finding therapeutic strategies to counteract the depression of breathing by anesthetics and pain-relievers depends on understanding what these cells do and how their activity is modified, and will save and improve the quality of the lives of Veterans.

VA involvement: The researchers who conducted this work included Edward J Zuperku, EA Stuth, AG Stucke, and FA Hopp, who held appointments and conducted their research at the Clement J Zablocki Department of Veterans Affairs Medical Center in Milwaukee, WI. VA also provided Merit Award funding in support of this work.

Reference: Prkic I, Mustapic S, Radocaj T, Stucke AG, Stuth EA, Hopp FA, Dean C, Zuperku EJ. Pontine mu-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs. J Neurophysiol. 2012;108:2430–41. [PMC free article] [PubMed]

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Project 6.

Headline: A wearable artificial pancreas

Bottom Line: VA research with dogs was the basis for the development of a wearable artificial pancreas for people with diabetes. Nearly one in four Veterans receiving care in the VA has diabetes and stands to benefit as this technology continues to develop, improving the control of blood sugar levels without repeated insulin shots.

What Veterans face: About 5.7 million Veterans have diabetes. They have to be constantly vigilant about their diet, and many have to manage multiple daily finger pricks to monitor blood glucose levels and insulin injections to control those levels. The better they control their blood glucose levels, the lower their risks of developing the many health complications that are associated with poorly controlled diabetes (including cardiovascular complications, nerve damage, kidney damage, eye complications, and problems with healing).

What VA research did, and when: Beginning in the 1980s, VA supported research with dogs that was instrumental to the quest to improve the lives of Veterans with diabetes by developing a wearable artificial pancreas. VA provided expert consultants in the field of diabetes and insulin secretion, and core services to analyze the effectiveness of the devices, as well as being responsible for the veterinary and husbandry care for the dogs. This was a close collaboration on proprietary work with a private industry sponsor to find a better way to control blood sugar levels more easily and more accurately than is possible with finger sticks and injections. The device was approved by FDA in September 2016 and is now used in VA patients with serious diabetes.

VA involvement: The researchers who were involved in this work included Seymour Levin, who held an appointment at the VA Greater Los Angeles Healthcare System in Los Angeles, CA, and was instrumental in establishing and supporting the collaborative relationship between the VA and the private industry researchers involved in this effort.

Reference: Soon-Shiong P, Feldman E, Nelson R, et al. Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets. Transplantation. 1992;54(5):769–774. [PubMed]

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Project 7.

Headline: Finding better drugs to treat urinary tract infections

Bottom Line: VA research in dogs showed that drugs like Ciprofloxacin (“Cipro”) can safely get to and act on bacteria in tissues of the urinary tract. This justified trying them for treating bacterial prostatitis or other urinary tract infections (UTIs) in human subjects. The new treatment options that these led to were especially important to Veterans with spinal cord injuries because of their increased risk of UTIs – one study found that 40% of them had had UTIs over 13 years.

What Veterans face: Over 30,000 Veterans per year are diagnosed with urinary tract infections (UTIs). Those with spinal cord injury are roughly 10 times more likely than others to acquire UTIs because their injury interferes with bladder emptying. The antimicrobial drugs available in the first half of the 20th century were not very effective for UTIs, and had serious side effects. Drugs that became available in the 1950s were more effective and safer, but bacterial resistance to them developed quickly.

What VA research did, and when: VA research with dogs in 1983-1987 provided evidence that a new class of antimicrobial drugs, the fluoroquinolones, could penetrate the tissues of the urinary tract, including the prostate gland, and were effective against the bacteria that cause UTIs. This work could not be done with smaller animals because it depended on being able to collect as series of samples large enough to analyze, of uncontaminated prostate secretion, prostatic interstitial fluid, urine, and blood while the drugs were administered, as well as tissue specimens. The results of this research showed that it was reasonable to study the new drugs in clinical trials with human subjects. Those clinical trials in turn resulted in the establishment of drugs like ciprofloxacin (“Cipro”) as improved standard treatments for UTIs.

VA involvement: The researchers who conducted this work included PO Madsen, who held an appointment and conducted his research at the William S Middleton Memorial Veterans Hospital, in Madison, WI.

Referance: Gasser TC, Graversen PH, Madsen PO. Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids. Antimicrob Agents Chemother. 1987 Jul;31(7):1010–1013. [PMC free article] [PubMed]

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Project 8.

Headline: Understanding how the pancreas works

Bottom Line: Insulin was discovered through research with dogs in Canada in the early 1900s, changing diabetes from a death sentence to a manageable disease. Some 5.7 million Veterans (almost 1 in 4) have diabetes. VA research continued efforts to understand how insulin secretion by the pancreas is controlled.

What Veterans face: About 5.7 million Veterans have diabetes. This means that their blood glucose levels are not appropriately controlled by automatic adjustments in the rates of secretion of insulin and glucagon by the pancreas. Current treatment involves various efforts to manage the blood glucose levels artificially, by lifestyle changes and by administration of insulin. Inadequacies in that management are associated with increased risks of developing many health complications, including cardiovascular complications, nerve damage, kidney damage, eye complications, and problems with healing).

What VA research did, and when: Dogs have been important to diabetes research ever since insulin was first discovered in dogs (work that was awarded the Nobel prize in 1923). Although much diabetes research has been done with mice and rats, it is known that the microstructure of the pancreas – the arrangement of the cells in islets – in humans is quite different from in rodents, and more like that in dogs. That’s why VA research in the 1980s and 1990s, which showed that the cells in the pancreas communicate with each other by signals carried in the blood, was done with dogs. This is important to understanding how the pancreas coordinates the secretion of insulin with other pancreatic functions. Finding ways to adjust that coordination is another approach, other than injecting insulin, to managing the insulin that controls blood glucose levels.

VA involvement: The researchers who conducted this work included John I Stagner and Horacio J Adrogué, who held appointments and conducted their research at the Robley Rex VA Medical Center in Louisville, KY, and the Michael E DeBakey VA Medical Center in Houston, TX. VA also provided Merit Review funding to support this work.

Reference: Stagner JI, Samols E, Bonner-Weir S. beta----alpha----delta pancreatic islet cellular perfusion in dogs. Diabetes. 1988;37:1715–1721. [PubMed]

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Project 9.

Headline: ACE-inhibitors and beta blockers treat heart failure

Bottom Line: VA research with dogs added to understanding of why the heart may fail to pump properly and how it can be helped by Beta blockers and ACE inhibitors. In 2010 alone, the VA treated 117,870 Veterans with heart failure.

What Veterans face: Heart failure is when the heart is not able to pump out efficiently the blood that the body needs. This makes fluid accumulate in the lungs (which causes shortness of breath) and in the lower parts of the body (which is noticeable as swelling). Along with these, dizziness, fatigue, and weakness all limit what a person with heart failure can do, interfere with the quality of life, and can become life-threatening.

What VA research did, and when: VA research with dogs in the 1980s-2000s helped to sort out the mechanisms responsible for heart failure. Careful observations were made of how the heart responded to various drugs that were known to interfere with specific mechanisms, and the research resulted in identifying drugs that are now standard clinical treatments for heart failure. It was important that this work be done with dogs because the size and geometry of the heart matter. This research has led to an increased understanding of the mechanisms of heart diseases and improved treatment regimens for the 60,000 Veterans who are newly diagnosed with heart failure each year. VA involvement: The researchers who conducted this work included Michael R Zile, Blase A Carabello, and Francis G Spinale, who held appointments and conducted their research at the Ralph H Johnson VA Medical Center in Charleston, SC. VA also provided funding to support this work.

Nagatsu M, Zile MR, Tsutsui H, Schmid PS, DeFreyte D, Cooper G, Carabello BA. Native β-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function. Circulation. 1994;89:818–826. [PubMed]

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Project 10.

Headline: Finding the key to both narcolepsy and opioid addiction

Bottom Line: VA research with dogs identified the specific changes in specific places in the brain that cause narcolepsy. The opposite brain changes have now been observed with exposure to opioids.

This means that continuing research to find better ways to treat people with narcolepsy is now likely to be valuable to understanding and treating opioid use disorder as well.

What Veterans face: An estimated 10,000-20,000 Veterans have narcolepsy. The overwhelming daytime sleepiness it causes is bad enough itself, but the consequences of that sleepiness only make things worse. Narcolepsy interferes with normal function at work or school, places the person at high risk when driving or operating other machinery, and complicates social interactions, leading to social isolation. Current treatment is limited to certain stimulant drugs that can control the sleepiness temporarily, but have side effects. An estimated 131,000 Veterans struggle with opioid use disorder, and are roughly twice as likely as others to die of opioid overdoses.

What VA research did, and when: Beginning in the 1980s, VA research has identified the brain regions and the changes in those regions, that are responsible for narcolepsy. This was made possible by research with a unique colony of dogs at the VA, that naturally develop narcolepsy. Ongoing research is focused on finding ways to reverse or counteract the changes that cause narcolepsy.

Recent work with brain tissue willed to research by human donors has shown that the same brain regions responsible for narcolepsy show the opposite changes in people with opioid addiction. Work with mice has shown that those changes develop with long-term exposure to morphine. This suggests that the research to help Veterans with narcolepsy might turn out to help Veterans with opioid abuse disorder as well.

VA involvement: The researchers who conducted this work included Jerome M Siegel, LN Boehmer, M-F Wu, TC Thannickal, J John, L Shan, L Ramanathan, R McGregor, and KT Chew, who held appointments and conducted their research at the Veterans Administration Greater Los Angeles Healthcare System in Los Angeles, CA. VA also provided funding to support the work.

Reference: Boehmer LN, Wu MF, John J, Siegel JM. Treatment with immunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptom severity. Exp Neurol2004;188:292–299. [PubMed]

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Project 11.

Headline: Managing gastrointestinal side effects

Bottom Line: VA research with dogs characterized the contractions of the gastrointestinal system and how they are changed by antibiotics, immunosuppressive drugs, and radiation therapy that have GI side effects, so that strategies to limit those side effects could be developed.

What Veterans face: Gastrointestinal side effects – nausea, vomiting, abdominal cramping, diarrhea

– are well known with some antibiotics, immunosuppressants, and radiation exposure. Better strategies are needed to limit these side effects in Veterans who need treatment with these agents, or who are otherwise exposed to radiation.

What VA research did, and when: Gastrointestinal (GI) side effects are related to disorders in the control and coordination of the contractions of the GI system.  Not enough contraction often results in nausea and vomiting, while too much contraction leads to cramping and diarrhea. Understanding the mechanisms that control and coordinate the contractions is key to finding ways to restore normal function. VA research in the 1980s and continuing into the 2010s identified some of the mechanisms involved, and sorted out how they are affected by treatments that have GI side effects. This work was done with dogs because the instruments needed to measure the contractions are too big for rodents, and because some of the mechanisms that were examined exist in humans and dogs, but not in rodents.

VA involvement: The researchers who conducted this work included Mary F Otterson, Shawn C Leming, and CJ Fox, who held appointments and conducted their research at the Clement J Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI.

Reference: Otterson MF, Leming SC, Fox CJ, Moulder JE. Propagation of giant migrating contractions between the small intestine, cecum and colon during radiation. Neurogastroenterol Motil. 2010 Aug;22(8):919-26 [PubMed]

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Project 12.

Headline: Safe and accurate diagnosis of kidney blood flow

Bottom Line: VA research with dogs validated the use of ultrasound to measure kidney blood flow, making it much easier to identify the Veterans who can benefit from new treatment options for preserving kidney function and controlling hypertension.

What Veterans face: Narrowing of the blood vessels that supply the kidney (renal artery stenosis) can interfere with the function of the kidney, and result in kidney damage and hypertension. Earlier methods for diagnosing this narrowing were not very accurate, or were expensive and required injecting dyes and exposing the patient to radiation. This made it hard to know exact numbers, but estimates are that 70,000 – 400,000 Veterans have renal artery stenosis.

What VA research did, and when: VA research with dogs, published in 1984, helped to validate the accuracy of measurements made by a noninvasive ultrasound method, compared to measurements made by an electromagnetic flowmeter placed surgically on the artery. Ultrasound is now established as a standard clinical method for diagnosing renal artery stenosis.

VA involvement: The researchers who conducted this work included Pratap S Avasthi, who held an appointment at the Raymond G Murphy VA Medical Center in Albuquerque, NM.

Refereance: Avasthi PS, Greene ER, Voyles WF, Eldridge MW. A comparison of echo-Doppler and electromagnetic renal blood flow measurements. J Ultrasound Med. 1984 May;3(5):213-8. [PubMed]

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Project 13.

Headline: Improving life by restoring the ability to cough

Bottom Line: Research with dogs made it possible for Veterans with spinal cord injuries to breathe without a ventilator and to cough effectively, dramatically reducing hospitalizations for potentially lethal pneumonia and improving their quality of life. VA research has now developed an improved approach to cough stimulation that can be used in people for whom the existing system would be intolerably painful.

What Veterans face: Over 20,000 Veterans are living with spinal cord injuries (SCIs) that make it hard for them to produce a coordinated cough that is strong enough to be useful. Strokes (an estimated 15,000 Veterans each year) and diseases like ALS (more likely in Veterans than others) can do the same thing. This puts them at high risk of potentially lethal respiratory infections and pneumonia. It also severely limits their quality of life because they have to always have someone present who can provide suction at any time, a noisy procedure that causes a commotion in public.

What VA research did, and when: Beginning in the 1990s, this group of researchers has conducted research with dogs to develop ways to restore respiratory function by stimulating the respiratory muscles in people with spinal cord injuries (SCIs). This work had to be done with dogs because the arrangement of the cells in the dog spinal cord is similar to that in humans, and because the devices being developed were too big to use in smaller animals. When the work with dogs showed that the approach was reasonable to try in people, many Veterans were among the volunteers who participated in the clinical trials. Stimulators acting on the nerves that control the respiratory muscles, or directly on the diaphragm, have now replaced bulky mechanical ventilators and make more natural breathing possible for over 1000 people worldwide. The same researchers then continued their research with dogs to develop a way to stimulate the muscles in the pattern that produces an effective cough. The resulting Cough Stimulator was also tested with Veterans who volunteered for the clinical trials, and is now in use clinically, reducing the incidence of respiratory infections and improving quality of life, and dramatically reducing the costs of care for these people. Because the Cough Stimulator can only be used in people with no feeling below the level of their injury, VA began supporting the researchers in 2014 to refine the system so that the electrical stimulation that is needed will not be painful for those who have sensation in their respiratory muscles. This will make it useful for more Veterans with SCI, as well as others who have difficulty coughing because of strokes or ALS. This work is now moving toward clinical trials in people.

VA involvement: The researchers who conducted this work included Krzysztof E Kowalski, JR Romaniuk, SW Brose, and MA Richmond, who held appointments and conducted their research at the Louis Stokes Cleveland Veterans Administration Medical Center Cleveland, OH. VA also provided Merit Award funding in support of this work.

Reference: Kowalski KE, Romaniuk JR, Brose SW, Richmond MA, Kowalski T, DiMarco AF. High frequency spinal cord stimulation-New method to restore cough. Respir Physiol Neurobiol. 2016 Oct;232:54-6. doi: 10.1016/j.resp.2016.07.001. Epub 2016 Jul 6. [PubMed

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Project 14.

Headline: Hip Surgery Helps People and Dogs

Bottom Line: Improved techniques for surgery to correct problems that develop after hip replacement. This is necessary in about 10% of people who have hip replacements, or almost 17,000 Veterans.

What Veterans face: Ten to 15 years after successful hip replacement surgery, normal wear and tear can make the artificial hip start to loosen. Infection can make it happen earlier. Hip revision surgery may be done to correct this, but is difficult because the original surgery to put in the artificial hip reduced the amount of bone there is for the surgeon to work with when revision is needed.

What VA research did, and when: VA research in the 1990s worked out how best to use bone grafts to rebuild hip joints and then attach hip muscle to these grafts. This benefits not only Veterans who need hip replacements, but also dogs with hip dysplasia, which can also be treated by hip replacement.

VA involvement: The researchers who conducted this work included John Heiner, who held appointments and conducted their research at the William S. Middleton Memorial Veterans Hospital Madison, WI.

Reference: Heiner JP1, Manley P, Kohles S, Ulm M, Bogart L, Vanderby R Jr. Ingrowth reduces implant-to-bone relative displacements in canine acetabular prostheses. J Orthop Res. 1994 Sep;12(5):657-64. [PubMed]

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Project 15.

Headline: The nervous system and diabetes

Bottom Line: Diabetes, which affects almost 1 in 4 Veterans, is the result when the blood sugar levels are not adequately controlled. Those levels are adjusted by hormones secreted by the pancreas, and there are nerves that act on the pancreas to adjust its secretions. VA research with dogs Increased understanding of what those nerves do.

What Veterans face: Insulin was discovered through research with dogs in Canada in the early 1900s, changing diabetes from a death sentence to a manageable disease. For the 5.7 million Veterans with diabetes, blood glucose levels are not appropriately controlled by automatic adjustments in the rates of secretion of insulin and glucagon by the pancreas. Current treatment involves various efforts to manage the blood glucose levels artificially, by lifestyle changes and by administration of insulin.

Inadequacies in that management are associated with increased risks of developing many health complications, including cardiovascular complications, nerve damage, kidney damage, eye complications, and problems with healing. Diabetes is the leading cause of blindness, end-stage renal disease, and amputation for VA patients

What VA research did, and when: Dogs have been important to diabetes research ever since insulin was first discovered in dogs (work that was awarded the Nobel prize in 1923).  Understanding how the rates of secretion of insulin and glucagon by the pancreas are normally adjusted to meet what the body needs is an important approach to finding better ways to treat diabetes. VA research in the 1990s focused on how the nervous system controls insulin and glucagon secretion from the pancreas. The investigators examined the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting beta(2)-adrenergic mediation, which was confirmed by beta-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and beta-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. The conclusions were1) the insulin response to showing food is mediated by the beta(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(2)-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone.

Although much diabetes research has been done with rats and mice, these studies could only be done with larger animals in which the instrumentation needed for the research would fit, and from which the necessary number and volume of blood samples could be collected and analyzed. This basic research led to a better understanding of the physiologic mechanisms that control blood sugar levels. VA involvement: The researchers who conducted this work included Gerald J Taborsky, Jr, Lambertus Benthem, Thomas O. Mundinger, and Peter J Havel, who held appointments and conducted their research at the Veterans Affairs Puget Sound Health Care System in Seattle, WA. VA also provided Merit award funding in support of this work.

Reference:  Havel PJ, Mundinger TO, Taborsky GJ Jr. Pancreatic sympathetic nerves contribute to increased glucagon secretion during severe hypoglycemia in dogs.  Am J Physiol. 1996 Jan;270(1 Pt 1):E20-6. [PubMed]

Benthem L1, Mundinger TO, Taborsky GJ Jr. Parasympathetic inhibition of sympathetic neural activity to the pancreas. Am J Physiol Endocrinol Metab. 2001 Feb;280(2):E378-81. [PubMed]

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Project 16.

Headline: Treating cardiac arrhythmias

Bottom Line: Developed some of the key instruments and techniques for ablation, a way to cure disturbances of heart rhythm that some 400,000 Veterans have, by selectively destroying abnormal heart tissue. This is now used routinely in the cardiac clinic.

What Veterans face: Cardiovascular disease refers to conditions that affect the heart or blood vessels. These are the leading cause of hospitalization in the VA health care system and are also a major cause of disability. Cardiac arrhythmia is a heart condition in which the heart bests too fast, too slow, or irregularly. Untreated arrhythmias may have serious consequences, such as heart attack and stroke.

What VA research did, and when: VA research with dog models in the 1990s and 2000s was crucial in the development of cardiac ablation as a way to treat cardiac arrhythmias. Cardiac ablation involves threading a long, flexible tube through a vein or artery all the way to the heart. Energy, in the form of heat (radiofrequency ablation - similar to microwave heat) or extreme cold (cryoablation), is used to scar or destroy abnormal heart tissue, which cures the arrhythmia. The VA research with dogs contributed to the evolution of the instruments used and the optimization of the intensity and duration of the ablation energy applied. This has become a routine procedure for the clinical treatment of cardiac arrhythmias. Dogs also have cardiac arrhythmias, so these advances have benefited dogs as well as humans.

VA involvement: The researchers who conducted this work included Warren M Jackman, Kenichiro Otomo, Hiroshi Nakagawa, and William S Yamanashi, who held appointments and conducted their research at the Oklahoma City VA Health Care System in Oklahoma City, OK. VA also provided Merit Award funding in support of this work.

Reference: Antz M1, Otomo K, Nakagawa H, Yamanashi WS, Jackman WM, Kuck KH. Radiofrequency catheter ablation with the split-tip electrode in the temperature-controlled mode. Pacing Clin Electrophysiol. 2001 Dec;24(12):1765-73. [PubMed]

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Project 17.

Headlines: Using cell scaffolds to treat vascular injuries

Bottom Line: Developed bioengineered vascular scaffolds to improve blood flow for transplanted tissue and grafts.

What Veterans face: Leg and arm wounds, with blood vessel injury and high amputation rates, occur in trauma victims and are especially common in injured Service Members from the Iraqi/Afghanistan war (Operations Enduring Freedom/ Iraqi Freedom/New Dawn; OEF/OIF/OND). The high number of limb injuries among OEF/OIF/OND Veterans and their long-term, complex care requirements pose a significant challenge to the VA. Combat-related vascular injuries are present in 12% of this cohort, a rate 5 times higher than in prior wars, and extremity injuries comprise 50-60% of casualties.

What VA research did, and when: There are three principal therapeutic strategies for treating diseased or injured tissues in patients: (1) implantation of freshly isolated or cultured cells; (2) implantation of tissues assembled in vitro from cells and scaffolds; and (3) induction of in situ tissue regeneration. VA research with dogs in 1990s and 2000s focused on bioengineering vascular scaffolds that would support tissue transplants and grafts by providing the blood flow needed to supply nutrients and gas exchange. Scaffolds are designed to mimic the biochemical and biomechanical environment that supports cell viability and phenotypic characterization, so Understanding the interaction between cells and scaffolds is fundamental to improving tissue engineering strategies.

Smooth muscle cells (SMCs) were obtained from canine carotid arteries and identified and expanded using explant cell culture techniques. Dog vascular tissue were used because of its similarities to human tissue and had been used previously by this research group. Live phase-contrast imaging, confocal fluorescent and reflection imaging were used to visualize the morphological structure of both the cells and the collagen fibers, which facilitated a better understanding of the mechanism of scaffold remodeling and represents an effective tool to investigate the interaction between cells and scaffold in detail at the microscale level.

VA involvement: The researchers who conducted this work included Howard P Greisler, Eric M Brey, Kathryn J Jones, Thomas D Alexander, and Vicki A Husak, who held appointments and conducted their research at the Edward J Hines Jr VA Hospital in Hines, IL. VA also provided Merit Award funding in support of this work.

Reference: Pang Y1, Wang X, Ucuzian AA, Brey EM, Burgess WH, Jones KJ, Alexander TD, Greisler HP. Local delivery of a collagen-binding FGF-1 chimera to smooth muscle cells in collagen scaffolds for vascular tissue engineering.  Biomaterials. 2010 Feb;31(5):878-85. doi: 10.1016/j.biomaterials.2009.10.007. Epub 2009 Oct 23. [PubMed]

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Project 18.

Headline: Work with pet dogs leads to vaccines against melanoma for dogs and humans.

Bottom Line: In people and dogs, once melanoma spreads to distant sites it is usually incurable. VA research with dogs has led to vaccines for both dogs and humans, against this deadly cancer.

What Veterans face:  Melanoma is the most dangerous form of skin cancer and kills over 9,300 people a year in the US. The main cause of melanoma is the skin being exposed to too much ultraviolet light from the sun, leading to DNA damage and cancer. Veterans have a high rate of melanoma and have additional risks than the general population because many of them served in places closer to the equator than most of the US (such as Iraq and Vietnam) where they were exposed to high levels of ultraviolet light. Melanoma is now the fifth most commonly diagnosed cancer among Veterans.

What VA research did, and when: VA research with dogs, beginning in the 1990s and still ongoing, has been focused on finding better ways to treat melanoma. Although some research on treatments for melanoma has been done with pigs and mice, it is known that spontaneous melanoma in people behaves more like spontaneous melanoma in dogs, in how it responds to certain promising treatments. This means that research with dogs, to study these treatments is much more likely to be useful to humans, as well as to dogs. So far, this research has already led to the development of experimental vaccines against melanoma. VA has now awarded the researcher funding to develop better immunotherapies and protocols combining those with radiation therapy to optimize their effectiveness.

VA involvement: The researchers who conducted this work included Mark Albertini, who now holds an appointments at the William S Middleton Memorial- Veterans Affairs Medical Center in Madison, WI, and has been awarded VA Merit funding in support of the continuation of this work.

Reference: Zuleger CL, Kang C, Ranheim EA, Kurzman ID, Macklin MD, Newton MA, Wolchok JD, Vail DM, Eriksson E, Albertini MR. Pilot study of safety and feasibility of DNA microseeding for treatment of spontaneous canine melanoma. Vet Med Sci. 2017 May 22;3(3):134-145. doi: 10.1002/vms3.65. eCollection 2017 Aug. [PubMed]

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Project 19.

Headline: Gene therapy for canine immune deficiency disease may help people

Bottom Line: Identified the genetic basis for an immune deficiency disorder, leukocyte adhesion deficiency. This was the basis for the development of gene therapy to treat this disorder.

What Veterans face: Leukocyte adhesion deficiency type 1 is estimated to occur in 1 per million people worldwide. Individuals who suffer from this disease develop frequent serious bacterial and fungal infections and have a shortened life expectancy.

What VA research did, and when: VA research in the 1990s studied dogs with canine leukocyte adhesion deficiency (CLAD), as a model for human leukocyte adhesion deficiency (LAD). This is a disorder of the immune system that leads to an increased susceptibility to infections. The VA researcher discovered that the genetic mutation that causes canine LAD is the same as in some humans with LAD. He then built on this work after he moved to the NIH in 2000, and has developed effective gene therapy to treat dogs with CLAD. Efforts are underway to develop treatments for LAD based on this work.

VA involvement: The researchers who conducted this work included Dennis Hickstein, who held an appointment at the Veterans Affairs Puget Sound Health Care System in Seattle, WA.

Reference: Kijas JM1, Bauer TR Jr, Gäfvert S, Marklund S, Trowald-Wigh G, Johannisson A, Hedhammar A, Binns M, Juneja RK, Hickstein DD, Andersson L. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics. 1999 Oct 1;61(1):101-7. [PubMed]

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Project 20.

Headline: Improved bladder control for individuals with spinal cord injury

Bottom Line: Developed and optimized electrode arrays for stimulating peripheral nerves to enhance bladder control for use in patients with spinal cord injury.

What Veterans face: Urinary retention is a serious urological problem associated with SCI and pelvic surgeries, or it may be idiopathic. Before 1940, most people with spinal cord injury (SCI) died from urinary tract infections in the first few months after injury. After the introduction of antibiotics in the 1940's, people started surviving longer, but renal complications continued to be a problem and kidney failure became the leading cause of death. With current management practices and periodic testing, things have improved greatly, and now fewer than 3% of people with SCI die from kidney failure.

What VA research did, and when: Earlier ways of using electrical stimulation to empty the bladder required spinal surgery and severing nerves involved for sensation, or large electrical signals that also caused contraction of leg muscles. VA research with dogs in the 2000s studied ways to reduce the amount of current needed, while also requiring only minimally invasive laparoscopic techniques. In an anesthetized animal model, the combination of identification of the pelvic plexus nerves in the inferior vesical neurovascular bundle and intraoperative testing and implantation was shown to be an effective neurosurgical technique. Implanting the barb electrodes with a needle in a bilateral and bipolar configuration was also shown to be effective. Common stimulation parameters included 15 to 25 mA, 40 pps, and a 400 [micro]s pulse duration applied for 3 s. These methods avoided the spread of the electrical current to leg and other skeletal muscles. It was important for this work to be done with dogs because the canine model is well-established and the size and design of the instrumentation could be readily used in humans.

VA involvement: The researchers who conducted this work included James S Walter, Larissa Bresler, Andrew Jahoda, John S Wheeler, and Thomas Turk, who held appointments and conducted their research at the Edward Hines Jr Department of Veterans Affairs Hospital in Hines, IL. VA also provided Merit Review funding in support of this work.

Reference: Bresler L, Walter JS, Jahoda A, Wheeler JS, Turk T, Wurster RD. Effective methods of pelvic plexus nerve and bladder stimulation in anesthetized animal model. J Rehabil Res Dev. 2008;45(4):627-37. [PubMed]

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Project 21.

Headline: A better way to repair intervertebral discs responsible for back pain

Bottom Line: Developed a way to repair damaged intervertebral discs, which are responsible for back pain experienced by roughly 13,000 Veterans each year, often related to their service-related repetitive heavy load bearing and carrying.

What Veterans face: Low back pain is an extremely common symptom, affecting almost three quarters of the population sometime in their life. While 90% of the population recover within 3 months, chronic back or leg pain in some patients leads to long-term physical disability and a reduced quality of life. Because there are currently no effective therapies to retard or reverse disc degeneration, a variety of surgical procedures have been developed to treat disc degeneration and back pain. Unfortunately, the procedures currently available often do not provide a satisfactory outcome.

What VA research did, and when: VA research with dogs in the 2000s investigated the hypothesis that (1) repair of the damaged disc is technically feasible; (2) autologous cells can be reproducibly cultured under defined and controlled conditions; (3) percutaneous delivery is possible; and (4) disc chondrocytes will integrate with the surrounding tissue, produce the appropriate intervertebral disc extracellular matrix, and potentially provide a functional solution to disc repair. The work was done with dogs because there is an established model of disc degeneration in dogs, and it was important to study discs that are similar in size to human discs. The goal of this study was to test the hypothesis that restoration of intervertebral disc morphology could be achieved by transplantation of cultured autologous chondrocytes into the nucleus pulposus. After transplantation, cultured intervertebral disc cells were viable, retained a capacity for proliferation in situ, demonstrated an ability to make appropriate matrix, and underwent expression consistent with the phenotypic demands of the anatomy. Autologous transplant in controlled conditions might represent the least hurdle to the clinic. It affords the least manipulation of a cell line, imposes little chance of immune rejection, and as a terminally differentiated lineage underscores the emphasis on integrating chondrocytes with the intention of repairing the intervertebral disc. Clinical trials of treatments based on this research are now underway.

VA involvement: The researchers who conducted this work included Timothy Ganey, who held an appointment and conducted his research at the Atlanta Veterans Affairs Medical Center, Atlanta, GA.

Reference: Ganey T, Libera J, Moos V, Alasevic O, Fritsch KG, Meisel HJ, Hutton WC. Disc chondrocyte transplantation in a canine model: a treatment for degenerated or damaged intervertebral disc.  Spine (Phila Pa 1976). 2003 Dec 1;28(23):2609-20 [PubMed]

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Project 22.

Headline: Breathing after spinal cord injury

Bottom Line: Advanced the technology for stimulating breathing muscles in Veterans with spinal cord injuries by improving electrical leads and methods of stimulating the breathing muscles.

What Veterans face: In 2009, a VA fact sheet reported that over 250,000 Americans were living with serous spinal cord injuries (SCIs) and disorders, of whom about about 42,000 were Veterans eligible for medical care and other benefits from VA. The diaphragm and muscles of the upper chest and abdomen are paralyzed in people with neck SCIs, so they cannot breathe or cough without help.

What VA research did, and when: VA research by this group in the 2000s and 2010s project contributed to optimizing ways to stimulate electrically the nerves supplying muscles used for breathing. This work had to be done with dogs because dogs are so similar to humans in terms of both size and anatomy. In particular, the nerves that control the specific respiratory muscles are arranged in dogs like they are in humans. Small animal such as mice and rats are simply too small for the devices under study. Pigs are large enough, but their anatomy is different so they have not become an established model for respiratory stimulation in humans. This work has contributed to the development of new devices to assist SCI patients.

VA involvement: The researchers who conducted this work included James S Walter, Robert B Dunn, Robert D Wurster, Franco Laghi, Scott Sayers, Sanjay Singh, and Christine Staunton, who held appointments and conducted their research at the Edward J Hines Jr Veterans Affairs Hospital in Hines, IL.

Reference: Walter JS, Dunn RB, Wurster RD, Laghi F. Microstimulators and intramuscular hook electrodes for the stimulation of respiratory muscles. J Spinal Cord Med. 2007;30(4):338-45. [PubMed]

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Project 23.

Headline: Strategies for preventing sudden cardiac arrest

Bottom Line: Increased understanding of why the heart’s beating can get out of control, beating at rates over 200 beats/min, and even becoming completely uncoordinated, and then what can be done to bring it back under control.

What Veterans face: Ventricular tachycardia (very high heart rates) and ventricular fibrillation (uncoordinated contraction of the heart muscle that is useless for pumping, also called cardiac arrest) are associated with sudden cardiac arrest (SCA). About half of all deaths due to heart disease are from SCA and for about half of these patients, SCA is the first indication of the heart disease. Heart disease remains the leading cause of death in the US with an estimated 600,000 people dying from heart disease in 2010, which represents 24 % of total deaths.

What VA research did, and when: VA research with dogs in the 2000s-2010s investigated T-wave alternans (TWA) as potential risk factor for lethal arrhythmia. This study found that intracardiac TWA number, magnitude, and discordance resulting from ischemia correlated with the onset of spontaneous ventricular tachycardia (VT) / ventricular fibrillation (VF) when one of the blood vessels that supplies the heart muscle gets blocked. This may be useful for predicting VF in patients with implanted devices, such as a pacemaker, and in identifying ways to prevent VT.

It is important that this work was done with dogs, because the arrangement of the blood vessels that supply the heart muscle, and the electrical properties of the heart muscle in dogs, mean that acute VT in dogs is similar to what is observed in human patients. Other large animals such as pigs do not have the collateral circulation that humans and dogs have to keep the heart tissue supplied when a blood vessel to some region of the heart gets occluded. In pigs, when a blood vessel to the heart was occluded VF frequently occurred before any data could be collected. The hearts of mice, rats, and rabbits are too small to accommodate the electrodes used for recording and mapping, and their geometry prevent VT or VF from occurring.

VA involvement: The researchers who conducted this work included James B Martins, who held an appointment at the Iowa City VA Health Care System in Iowa City, IA. VA also provided funding in support of this work.

Reference: Kwofie MA, Chaudhary AK, Martins JB. Association among intracardiac T-wave alternans, ischemia, and spontaneous ventricular arrhythmias after coronary artery occlusion in a canine model. Transl Res. 2011 Nov;158(5):265-72. doi: 10.1016/j.trsl.2011.07.001. Epub 2011 Aug 3. [PubMed]

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Project 24.

Headline: Stimulating the GI tract – a new approach to obesity

Bottom Line: Contributed to the development of techniques for applying mild electrical stimulation to the intestinal tract to control obesity, a problem for as many as 8 million Veterans, and to improve bowel function after spinal cord injury.

What Veterans face: Obesity is a huge public health problem in the United States. The total annual cost for treating obesity and its co-morbidities (diabetes, heart disease, hypertension) is over $147 billion. Veteran patients are even more frequently overweight or obese; one report suggests that 75% of veteran patients are overweight.

What VA research did, and when: Mild electrical stimulation of the intestinal tract was studied in dogs and other animals by VA researchers in the 2000s and 2010s, as a method for treating obesity, diabetes, decreased gastric and colonic motility, and other diseases of the digestive system. Because of the anatomical and physiological similarities between people and dogs, dogs are an important animal model for studying metabolic associated diseases. Like people, dogs are prone to obesity, and roughly 30% of the dogs in North America are significantly overweight, which predisposes them to many of the same health risks as people have. The results of this research has been used in humans to inhibit gastric contractions, gastric emptying, food intake, and to maximize weight loss. There is also growing evidence to suggest that electrical stimulation can be used to treat neurogenic bowel dysfunction after spinal cord injury.

VA involvement: The researchers who conducted this work, including Jiande DZ Chen, Yan Sun, Geng- Qing Song, and Yong Lei, who held appointments and conducted their research at the Veterans Affairs Medical Center in Oklahoma City, OK. VA also provided funding in support of this work.

Reference: Sun Y1, Song GQ, Yin J, Lei Y, Chen JD. Effects and mechanisms of gastrointestinal electrical stimulation on slow waves: a systematic canine study. Am J Physiol Regul Integr Comp Physiol. 2009 Nov;297(5):R1392-9. doi: 10.1152/ajpregu.00006.2009. Epub 2009 Aug 26. [PubMed]

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Project 25.

Headline: Identifying methods to treat atrial fibrillation.

Bottom Line: Improved understanding of how conditions that the heart is exposed to increase the risks of atrial fibrillation, a common complication after heart surgery.

What Veterans face: Cardiovascular disease is the leading cause of admission to VA Medical Centers. Atrial fibrillation (AF) is the most common heart arrhythmia (estimated 170,000–380,000 Veterans); one-third of heart surgery patients develop AF afterwards (postoperative AF). Veterans who suffer from Post-Traumatic Stress Disorder (PTSD) have a 13% greater risk of developing AF. AF significantly increases the risk of stroke. An estimated $6 billion per year are spent on AF in the United States.

The medical costs for patients with AF are reported to be roughly $9,000 more per year than for those without AF.

What VA research did, and when: Research performed with dogs in the 2000s-2010s improved understanding of how the electrical properties of the heart change when the heart muscle is damaged and heals, and how that then changes the likelihood of atrial fibrillation. The researchers worked with dogs because of similarities in the electrical characteristics of the heart in humans and dogs, and because the measurements that had to be made could only be made if the hearts were large enough. Their earlier work clarified what was needed for ablation (selective destruction of dysfunctional heart tissue) to be effective at stopping AF. More recent work by the same researchers is being supported by VA funding, and has shown how the changes in the geometry of the heart that develop when valves become leaky can increase the risks of AF. Work is now planned to find out how inflammatory cells and their products in the pericardial fluid increase the risks of AF, which will define specific targets in the fluid that can be treated to prevent postoperative AF in Veterans.

VA involvement: The researchers who conducted this work included Spencer Melby, who held an appointment at the VA St. Louis Health Care System. VA is providing Merit Review finding in support of continuing this work.

Reference: Ruaengsri C, Schill MR, Lancaster TS, Khiabani AJ, Manghelli JL, Carter DI, Greenberg JW, Melby SJ, Schuessler RB, Damiano RJ Jr. The hemodynamic and atrial electrophysiologic consequences of chronic left atrial volume overload in a controllable canine model. J Thorac Cardiovasc Surg. 2018 Nov;156(5):1871-1879.e1. doi: 10.1016/j.jtcvs.2018.05.078. Epub 2018 Jun 5. [PubMed]

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Project 26.

Headline: Glaucoma – the silent cause of vision loss

Bottom Line: Increased understanding of how to protect vision that is threatened by glaucoma, which has been diagnosed in some 1.5 million Veterans, and is a leading cause of blindness worldwide.

What Veterans face: Glaucoma is called the silent cause of vision loss because it usually starts without any symptoms and slowly progresses. Veteran over 60 are the highest risk group and hypertension (high blood pressure), a common problem in Veterans, is another risk factor. Without early detection and treatment, glaucoma will lead to blindness.

What VA research did, and when: Glaucoma is one of the most frequent blinding diseases affecting veteran populations. While different medical and surgical strategies are developed for reducing the intraocular pressure in patients with glaucoma, there are no known strategies apart from regulating the intraocular pressure that can effectively protect the function of the retina and optic nerve. This VA research was conducted in the 2010s to evaluate the molecular changes in the retina and optic nerve that are related to hereditary glaucoma. This work was done with dogs that have hereditary glaucoma, which is almost identical to the human condition. Because glaucoma in dogs is so similar to glaucoma in humans, and because the size and shape of canine eyes are comparable to those of human eyes, dogs have been particularly important to glaucoma research for over 50 years. The researchers found that the progressive increase in intraocular pressure, loss of optic nerve function and retinal ganglion cell loss of advanced glaucoma are accompanied by pronounced retinal inflammation, suggesting that treatments to control inflammation might be useful for protecting vision in individuals with glaucoma.

VA involvement: The researchers who conducted this work included Randy H Kardon, who held an appointment at the Iowa City Veterans Administration Center. VA also provided Merit Review funding in support of this work.

Reference: Grozdanic SD1, Kecova H, Harper MM, Nilaweera W, Kuehn MH, Kardon RH. Functional and structural changes in a canine model of hereditary primary angle-closure glaucoma. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):255-63. doi: 10.1167/iovs.09-4081. Epub 2009 Aug 6. [PubMed]

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Project 27.

Headline: Premature ventricular contractions impair heart function

Bottom Line: Showed that disturbances of heart rhythms can interfere with heart function, not just because of the rhythm but because of effects on how the heart muscle works.

What Veterans face: Extra beats, so-called “Premature Ventricular Contractions” (PVCs), are known to affect up to 25-50% of general population. PVCs have been frequently associated with heart failure and sudden cardiac death.

What VA research did, and when: A decade ago, there was a debate as to whether these Premature Ventricular Contractions (PVCs) have any consequences for heart function. VA research beginning in the 2000s and continuing to the present confirmed that frequent PVCs alone can weaken the heart even without detectable structural damage. This “PVC-cardiomyopathy” was designated a unique clinical entity by the American Heart Association in its 2016 Scientific Statement. Further work described how often PVCs have to occur to affect heart function, and the molecular changes that develop with PVCs. This research had to be done with dogs because of the similarities in the dog’s heart rate and heart size to those in humans; rodent hearts are too small and beat too fast. The electrical properties of the heart are also similar in dogs and humans, which are very different from those in pigs and sheep. Finally, because so much cardiac research over decades has been done with dogs, there is an extremely valuable body of knowledge about canine heart function and how it relates to human heart function, for researchers to continue to build on.

VA involvement: The researchers who conducted this work included Jose F Huizar, Karoly Kaszala, Jonathan Potfay, Anthony J Minisi, Edward J Lesnefsky, Qun Chen, and Kenneth A Ellenbogen, who held appointments and conducted their research at the Hunter Holmes McGuire VA Medical Center in Richmond, VA. VA also provided Merit Review Award funding in support of this work.

Reference: Huizar JF, Kaszala K, Potfay J, Minisi AJ, Lesnefsky EJ, Abbate A, Mezzaroma E, Chen Q, Kukreja RC, Hoke NN, Thacker LR 2nd, Ellenbogen KA, Wood MA. Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol. 2011 Aug;4(4):543-9. doi: 10.1161/CIRCEP.111.962381. Epub 2011 May 16. [PubMed]

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Project 28.

Headline: Mechanisms of PVC-cardiomyopathy

Bottom Line: Uncovered cellular mechanisms involved in the impairment of heart function induced by Premature Ventricular Contractions.

What Veterans face: Heart disease is the number-one killer of Americans, and the leading cause of hospitalization in the VA healthcare system. Extra heart beats, so-called “Premature Ventricular Contractions” (PVCs), are known to affect up to 25-50% of general population. PVCs have been frequently associated with heart failure and sudden cardiac death.

What VA research did, and when: Extra beats are recognized now as a cause of weak heart (PVC- cardiomyopathy). However, it is unclear why some patients do not develop cardiomyopathy despite frequent PVCs. VA research beginning in the 2000s and continuing to the present are identifying cellular mechanisms of PVC-cardiomyopathy, and baseline features that protect the heart from, or predispose it to, developing cardiomyopathy. This research had to be done with dogs because of the similarities in the dog’s heart rate and heart size to those in humans; rodent hearts are too small and beat too fast. The electrical properties of the heart are also similar in dogs and humans, which are very different from those in pigs and sheep. Finally, because so much cardiac research over decades has been done with dogs, there is an extremely valuable body of knowledge about canine heart function and how it relates to human heart function, for researchers to continue to build on. The understanding gained from this research provides a basis for developing therapies to prevent and to treat PVC-cardiomyopathy.

VA involvement: The researchers who conducted this work included Jose F Huizar, Michael O’Quinn, Karoly Kaszala, Kenneth A Ellenbogen, and Alex Y Tan, who held appointments and conducted their research at the Hunter Holmes McGuire VA Medical Center in Richmond, VA.

Reference: Narayan Gurukripa Kowlgi, MD, Daniel G. Jovin, Michael O’Quinn, MD, Karoly Kaszala, MD, Kenneth A. Ellenbogen, MD, Alex Y. Tan, MD and Jose F. Huizar, MD.  NEITHER IRREGULARITY NOR TACHYCARDIA ARE TRIGGERS FOR PVC-CARDIOMYOPATHY: COMPARING PERSISTENT ATRIAL AND VENTRICULAR ECTOPY IN AN ANIMAL MODEL https://www.heartrhythmjournal.com/article/S1547-5271(18)30250-9/pdf

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Project 29.

Headline: Role of the autonomic nervous system in cardiac arrhythmias

Bottom Line: Uncovered how Premature Ventricular Contractions disrupt the balance of the autonomic nervous system, which triggers more cardiac arrhythmias.

What Veterans face: Premature Ventricular Contractions (PVCs) or extra beats are known to affect up to 25-50% of general population based on ambulatory ECG recordings. When PVCs are frequent, they can induce a weakening of the heart muscle, known as PVC-cardiomyopathy (PVC-CM). PVC-CM is increasingly recognized as a major cause of heart muscle weakness. A retrospective study of 245 patients suggest that the prevalence of a PVC-cardiomyopathy is much higher that previously suspected, as they find that 67% of patient improved their abnormal heart function after eliminating frequent PVCs. PVCs can also trigger lethal arrhythmias, especially when the heart muscle has weakened. Therefore, the consequences of PVC-CM are heart failure and sudden arrhythmic cardiac death.

What VA research did, and when: The mechanism of how Premature Ventricular Contractions (PVCs) can weaken the heart and induce lethal arrhythmias remains unknown. One major hypothesis is that the frequent PVCs can disrupt the neural fine-tuning of heart function. VA research conducted in the last 2 years has shown that PVCs indeed induce a storm of unbalanced neural activity that triggers cardiac arrhythmias. The storm of activity persists even after PVCs are stopped, but can be prevented by toning down the neural communications between the heart and the brain. This then prevents the PVC-cardiomyopathy and further arrhythmias. This research could only be conducted with dogs because the canine heart most resembles the human heart in terms of its electrical conduction system, and its control by the autonomic nervous system. The electrical properties of the hearts of smaller animals such as rats and mice are very different from those of dogs and humans, and the cardiac and nervous anatomy and physiology of other large animal species such as pigs and sheep are so different from those of dogs and humans as to render them inadequate and irrelevant this work.

The results of this research have been presented at national scientific meetings, and reports for publication are in preparation. They provide a basis for designing novel therapies for PVC-CM based on autonomic modulation.

VA involvement: The researchers who conducted this work included Alex Y Tan, who held an appointment and conducted his research at the Hunter Holmes McGuire VA Medical Center in Richmond, VA.

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Project 30.

Headline: Nanoparticle delivery of agents to treat atrial fibrillation

Bottom Line: Demonstrated that postoperative Atrial Fibrillation can be safely and effectively prevented by delivering agents packaged in slow-release nanoparticles, to suppress the activity of cardiac nerves on the surface of the atria.

What Veterans face: Atrial Fibrillation (AF) is the most common arrhythmia worldwide in humans. It consists of an abnormal rhythm of the upper cardiac chamber. Most importantly, it is a major cause of stroke, heart failure, hospitalizations and death. AF occurs in up to 20-30% of patients that have undergone open-heart surgery, which is significantly higher than the normal population. These patients are then subjected to prolonged hospital stays, with an additional estimated in-hospital expenditure of $14,000 per patient, $57 milllion per annum in Virginia alone, and over a billion dollars worldwide. Preliminary results from our ongoing clinical study confirm that the risk of postoperative AF in our VA is at least 30%.

What VA research did, and when: Current therapies for postoperative AF are limited to pre-operative use of medicines that are only moderately effective. One approach to improving this involves disrupting cardiac nerves that are organized on the outside surface of the atria, and are known to cause AF. Currently, the disruption is accomplished by physically destroying the tissue, but it is hard to do this precisely enough not to damage nearby heart muscle as well. An alternative is to inject botulinum toxin (botox) into the area. VA research in the past two years has shown that chemicals to suppress nerve activity can be delivered in biocompatible nanoparticles for slow continuous release over weeks, and these can prevent AF in a postoperative canine model of AF, without any myocardial damage or side effects. This research was done with dogs because of the known similarities between the canine and human cardiac conduction system and nervous system. The hearts of smaller animals beat at much faster rates and are inherently resistance to AF, so it would not be possible to study AF with them. The research also could not have been done with other large animals like pigs, as cardiac conduction and nervous systems of pigs are significantly different from those of humans. The results of this research have been presented at national scientific meetings, and reports for publication are in preparation.

Nanoparticle ablation of cardiac nerves serves as a novel targeted therapy for postoperative AF, with the potential to benefit thousands of patients across the country and beyond by reducing risk of strokes and heart failure, hospitalizations and high costs of present treatments for AF. Now that this research with dogs has demonstrated the safety and efficacy of using nanoparticles to deliver agents that suppress nerve activity, the researchers are applying to conduct clinical trials, and their commercial partners are in the process of applying for FDA approval for clinical use.

VA involvement: The researchers who conducted this work included Alex Y Tan, who held an appointment and conducted his research at the Hunter Holmes McGuire VA Medical Center in Richmond, VA.

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