Showing posts with label heart transplant research. Show all posts
Showing posts with label heart transplant research. Show all posts

Tuesday, May 22, 2012

Top honor to cardiologist for advancing heart transplant medicine

By John Sanford Stanford School of Medicine

How do you keep a heart-transplant recipient alive and healthy for the long term?

That was the challenge taking shape by the mid-1970s, when Sharon Hunt, MD, was a cardiology fellow at Stanford Hospital. Meeting that challenge has since defined her career and earned her one of the most prestigious awards in the field of heart-transplantation medicine: the International Society for Heart and Lung Transplantation award for lifetime achievement, which she accepted in April in Prague.

Cardiologist Sharon Hunt received in April a lifetime achievement award from the International Society for Heart and Lung Transplantation. Photo: Norbert von der Groeben

 “It’s the biggest honor I’ve ever had,”

Hunt said. Hunt arrived at Stanford as a first-year medical student in the fall of 1967. A few months later, Stanford cardiac surgeon Norman Shumway, MD, and his team performed the first adult human heart transplantation in the United States. The success of that feat (the patient survived 14 days) inspired other heart surgeons across the nation to try their hand at the operation. However, most recipients survived just a few weeks or months, and an unofficial moratorium on the procedure went into effect in 1970. Over the next decade, Shumway’s team, which ignored the moratorium, made steady progress in refining its surgical techniques, introducing the heart biopsy for assessment of acute organ rejection and determining the viability of hearts procured and then transported to a transplant center. By 1974, 40 percent of their patients were living for two years, and 26 percent were making it to three years.

“By the time I was finishing cardiology training, in 1977, the survival rates for transplant patients were getting to be substantial,” said Hunt, a cardiologist at Stanford Hospital & Clinics and professor of cardiovascular medicine at the School of Medicine. “The surgeons had always claimed care of these patients, but with longer survival rates they were getting opportunistic infections and other medical problems — things the surgeons didn’t want to deal with. So they started looking to cardiology trainees to supply medical care. Like lots of people in advanced medical training, I was looking for a niche, and this one looked promising.”

Hunt remained at Stanford after her fellowship in 1981 as a clinical assistant professor, forging a path in this burgeoning field. Since then, key advances in long-term postoperative care for heart recipients have stemmed largely from her research and clinical work.

“Even after the surgical technique for heart transplantation had been developed and operations had been done, the field was naïve: People didn’t know how to manage patients,” said cardiologist Michael Pham, MD, clinical associate professor of medicine. “How do you manage patients who will be on immunosuppressive medications for the rest of their lives? How do you balance the benefit of these drugs with their toxicities? How do you identify and treat patients who reject their transplanted hearts? These are some of the questions that Sharon has done more than anyone to answer.”

Indeed, heart-transplant patients face a host of diseases and complications that can set back or snuff out their delicate new lease on life. These are diseases such as cardiac allograft vasculopathy, in which the walls of the coronary arteries become thicker, obstructing blood flow; infection, cancer and kidney failure, all abetted by the powerful immunosuppressant that recipients take to prevent rejection; and many other complications, including high blood pressure and high cholesterol.

“Without Sharon, who took care of these transplant patients after figuring out their medications and complications, there would be no successful cardiac transplantation at all,” said Alan Yeung, MD, chief of cardiovascular medicine at Stanford Hospital and the Li Ka Shing Professor in Cardiology. Heart recipients’ survival rates have vastly improved since the early days of transplants. At Stanford, the three-year survival rate was 78 percent for adults receiving a first heart transplant between 2006 and 2008, according to the Scientific Registry of Transplant Patients.

The lifetime achievement award also recognizes Hunt for having trained many international leaders in the field of post-transplant cardiology. She has made significant scientific contributions (she has authored or co-authored close to 200 peer-reviewed articles); headed the recent development of international guidelines on the care of heart-transplant recipients; and helped pave the way to the certification of the subspecialty in advanced heart failure and transplant cardiology by the American Board of Internal Medicine.

The International Society for Heart and Lung Transplantation has given only five lifetime achievement awards in its 31-year history. Two have gone to Hunt’s late Stanford colleagues and mentors, Shumway and Margaret Billingham, MD, a renowned cardiac pathologist. The others went to Sir Magdi Yacoub, MD, an Egyptian-born cardiothoracic surgeon, and the late Keith Reemtsma, MD, a pioneering transplant surgeon. 

Among dozens of other accomplishments, Hunt has also served as chair of the American College of Cardiology/American Heart Association Guidelines Committee to Rewrite Heart Failure Guidelines, which Pham called “probably the most commonly quoted guidelines ever in the field of cardiovascular medicine,” and as associate editor of the textbook Hurst’s The Heart and the Journal of Cardiac Failure.

“Through the years, she has just been incredibly productive. Her trainees comprise the leaders and experts in the field of heart transplant cardiology around the world,” said Bruce Reitz, MD, the Stanford cardiothoracic surgeon who performed the first successful heart-lung transplant. “She’s also a wonderful colleague — the ideal colleague — who is very responsive, with solutions and suggestions that are very helpful. You know that when a patient is under her care, that patient is getting the absolute best care.”

Hunt said the two things she likes most about her job are mentoring cardiology fellows and taking care of patients, “though I still don’t like reading EKGs or being on-call all night”

What about her next steps? “I think I’ll keep doing what I’m doing for the next few years,” she said. John Sanford is a writer in the communications office at Stanford Hospital & Clinics. Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital.

For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu/.


“You Have the Power to Donate Life – to become an organ and tissue donor Sign-up today! Tell Your Loved Ones of Your Decision”
Australia, register at Australian Organ Donor Register
New Zealand, register at Organ Donation New Zealand
South Africa, http://www.odf.org.za/
United States, donatelife.net
United Kingdom, register at NHS Organ Donor Register
Your generosity can save or enhance the lives of up to fifty people with heart, kidneys, liver, lungs, pancreas and small intestine transplants (see allotransplantation). One tissue donor can help by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant. Organs can save lives, corneas renew vision, and tissue may help to restore someone's ability to walk, run or move freely without pain. Life Begins with You.

Monday, September 12, 2011

Cardiac gene therapy shows promise to save lives

By Marie McCullough, Inquirer Staff Writer

In recent months, researchers in Philadelphia and beyond have reported success using gene therapy to treat common, intractable cardiac problems including heart failure, hardened arteries, and the racing heartbeat known as atrial fibrillation.

You probably haven't heard about these feats because they were in pigs, dogs, or sheep.

In the most complex mammal of all - humans - the results of cardiac gene therapy experiments have been encouraging, but inconclusive.

That's not unusual in the early stages of clinical testing, but it is frustrating for the dogged researchers who believe the field is close to a breakthrough. They foresee genetic fixes for the cardiac problems we now treat with drugs, surgery, implantable electrical devices, and heart transplants.

"I think cardiac gene therapy has great promise," said Steven R. Houser, director of Temple University School of Medicine's cardiovascular research center. "I think you'll see lots of things over the next few years."

At least 146 human trials of heart gene therapies are going on worldwide, making cardiovascular disease second only to cancer in terms of clinical testing, according to the Journal of Gene Medicine.

The hopes - and the hurdles - are high.

A little background: Gene therapy harnesses the insidious ability of viruses to slip their DNA into the cells they infect. Scientists use these viral transporters, or "vectors," to deliver genes that carry helpful, rather than harmful, instructions. Those instructions, in turn, tell the cell to make the proteins that carry out biological functions, such as fighting infection, digesting food, and sending pain signals.

This beguiling approach is harder than it might sound. It's difficult to get a vector to home in on cells in a particular tissue, never mind the right spot in the cell's genome. It's also difficult to keep the body's immune system from attacking the invading vector before the therapeutic DNA has time to work.

Today, 21 years after the approach was first tried in humans, there is still no government-approved gene therapy product.

There are, however, some impressive successes*. Just last month, a Penn team led by Carl June reported that leukemia regressed or disappeared in the first three patients to try an immune-boosting gene therapy - amazing results for an early test. Gene therapy also has worked well against a rare form of blindness and against a deadly inherited immune deficiency disorder - each caused by defects in a single gene.

In contrast, heart diseases, like most chronic ailments, involve the combined effects of many faulty genes. A big hurdle has been finding one gene that can override or undercut these many genetic miscues.

In recent years, genes that regulate calcium have emerged as promising targets for the mother of all heart diseases - heart failure.

While calcium is popularly thought of as a bone-hardening mineral, it is also a powerful cell-signaling molecule, playing a role in everything from cell death to the contractions of the heart muscle.

Those contractions weaken when the heart is damaged by a heart attack, toxic chemicals, a leaky heart valve, or the many other problems that lead to heart failure.

Heart failure symptoms - breathlessness, fatigue, fluid buildup - can be managed with drugs and surgery. But the disorder tends to be chronic and progressive, leading to 280,000 deaths and a tab of $40 billion every year.

In studies using pigs and sheep, a therapy using a gene called SERCA2a clearly improved the contraction of the left ventricle, the heart's main pumping chamber.

In humans, the power of SERCA2a is not so clear. A clinical trial led by University of Pennsylvania cardiologist Mariell Jessup gave low, medium, or high doses of the gene therapy or a placebo to 39 patients with advanced heart failure.

Only the high-dose group seemed to benefit, emphasis on seemed. After six months, only one of the nine high-dose patients had worsening heart failure, although none had improvement in heart pumping.

"It looked like patients with the high dose did less poorly. They had less death and deterioration," Jessup said of the results, published in June in the journal Circulation. "There was a signal [of effectiveness]. Which is about the best we can say."

Celladon, the La Jolla, Calif., biotech company that is trying to raise money to keep developing the SERCA2a product it calls Mydicar, was decidedly more upbeat.

The frequency of death, hospitalizations, and heart transplant "was dramatically lower and sustained for patients on high-dose Mydicar compared with placebo," declared the company's news release. "Furthermore, patients' ability to exercise ... and quality of life all improved."

Houser, the Temple researcher, is not convinced that the therapeutic SERCA2a gene was ever activated in the patients.

"I've studied calcium my whole life. I'd love it to work," he said. "But I think the data is equivocal. I'm not sure it had any benefit."

Meanwhile, Thomas Jefferson University researchers are developing a gene therapy that boosts a calcium-binding protein called S100A1. They believe it is even more promising than SERCA2a.

The S100A1 gene "seems to be like the coach of a football team" rather than just a player, said Jefferson physician Patrick Most, who has studied it for 15 years.

S100A1 is also involved in energy production, a crucial piece of the heart failure puzzle. The protein tells the cell's mitochondria - the so-called power plants that convert oxygen and food into energy-rich molecules - to step up production, Most said.

In June, Most and colleagues published a paper comparing S100A1 therapy to sham treatment in pigs with failing hearts. (A balloon catheter was used to block coronary blood flow, inducing a heart attack that led to heart failure in about two weeks.)

While the pigs that received fake treatment at two weeks were dead or dying within 14 weeks, pigs that received S100A1 not only stopped getting weaker, but their hearts' pumping ability went back to normal. "We did not expect such a dramatic response," Most said.

The researchers are now talking to the U.S. Food and Drug Administration about trying S100A1 in humans.

Most said they're also discussing a clinical trial of another gene therapy that relieved heart failure in pigs by inhibiting stress-response hormones.

Large mammals are biologically much closer to humans than rodents. So why is it hard to make the therapeutic leap from large animals to humans?

One reason, researchers have come to realize, is that making a big animal sick - inducing a heart attack, say - sets up a different disease process than the natural one in sick humans.

Sometimes, man and animal share virtually the same disease. At the Penn veterinary school, Meg Sleeper and her colleagues have used gene therapy in dogs with a type of inherited cardiovascular disease that also afflicts children, raising hopes for a pediatric clinical trial.

But often, an animal breakthrough doesn't translate.

Consider the work of Crystal, the Weill Cornell researcher. He has spent much of his career seeking a gene therapy for cardiac ischemia - a dangerous reduction in the cardiac blood supply caused by clogging and hardening of the arteries.

Patients with widespread blockages can't be treated with surgery to bypass problem vessels or a stent that props open a few vessels. So Crystal's team focused on a gene that spurs the growth of new blood vessels, a process called angiogenesis. "In experimental animal studies, it works very well," he said.

So well that in 1997, the drug company now called Pfizer signed a deal with a firm Crystal founded to develop "BioBypass." Industry analysts predicted the product would be generating $82 million in sales by 2005.

While the therapy did spur the growth of tiny vessels in human hearts, the growth did not improve heart pumping or exercise endurance.

Now Crystal is working on an angiogenesis gene therapy engineered to be "one-hundredfold more potent" than the body's natural version.

"We expect to start human trials in six to eight months," he said.

*NOTE - Lung transplantation and gene therapy
Dr. Shaf Keshavjee and his team in Toronto are having success using gene therapy to repair and recondition donor lungs for transplant. (currently only about 15% of donor lungs are usable due to tissue damage).

Working with pig and then human donor lungs, which were unsuitable for transplantation, the researchers first placed the lungs on the Toronto XVIVO Lung Perfusion System to warm them to normal body temperature. Then, using a specially engineered adenovirus vector -- a common cold virus -- the researchers used a bronchoscope to inject the vector with an added IL-10 gene through the windpipe into the human lungs.

The study found that lungs maintained on the Toronto Lung Perfusion System alone, the control group, did not deteriorate and remained stable. However, the donor lungs that received the gene therapy, in addition to the ex vivo perfusion, significantly improved their function with regards to blood flow throughout the lungs and their ability to take in fresh oxygen and get rid of carbon dioxide. The boosted IL-10 effect lasts for up to 30 days in the lung. The authors state that transplanting lungs which function better from the start would lead to more predictable, safer outcomes, shorter periods of mechanical ventilation and shorter intensive care unit stays for patients. Merv.

“You Have the Power to Donate Life – Sign-up today! to become an organ and tissue donor
Tell Your Loved Ones of Your Decision”
Australia, register at Australian Organ Donor Register
New Zealand, register at Organ Donation New Zealand
South Africa, http://www.odf.org.za/
United States, organdonor.gov
United Kingdom, register at NHS Organ Donor Register
Your generosity can save or enhance the lives of up to fifty people with heart, kidneys, liver, lungs, pancreas and small intestine transplants (see allotransplantation). One tissue donor can help by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant. Organs can save lives, corneas renew vision, and tissue may help to restore someone's ability to walk, run or move freely without pain. Life Begins with You