Johns Hopkins, Building a Better Heart

In 1982 William DeVries, a cardiac surgeon at the University of Utah Hospital, successfully implanted an artificial heart in a patient who was suffering from end-stage heart failure. The recipient lived for 112 days with the device, designed by Robert Jarvik. Thirty years later, we've cloned sheep, developed the Internet, mapped the human genome, and progressed from LPs to CDs to MP3s, but we still haven't created an artificial heart that can sustain life for longer than a few months. "If you think about technologies in general and how they've advanced in the past three decades, I don't think you'd say that artificial heart technology has progressed at a pace that's appropriate for the amount of time that has passed," says T.E. "Ed" Schlesinger, dean of Johns Hopkins' Whiting School of Engineering. So what's the holdup? The challenges of creating an artificial heart that can "beat" an average of 35 million times a year for multiple years like a real heart are myriad. There are problems to solve regarding biocompatibility, power supply, blood flow, pumping systems, control mechanisms. Should the heart be fabricated from synthetic materials, muscle tissue grown from stem cells, or a combination of both? Does it have to pump like a real heart, or should it rely on a system of continuous flow, as current heart-assist devices do? Last winter, more than 160 people from the Johns Hopkins community and beyond attended the first Hopkins Heart Symposium. The purpose was to kick off a 10-year, $100 million-plus collaboration between doctors, engineers, and systems experts at Johns Hopkins to build the world's first permanent totally artificial heart. It was a goal first proposed a year earlier by Duke Cameron, a professor of surgery and chief of Cardiac Surgery at the School of Medicine. William DeVries himself was the keynote speaker, while Johns Hopkins physicians presented talks on subjects with titles like "Heart Failure 101" and "Stem Cells and Tissue Engineering." Engineers spoke about the mechanics of pumping blood. Since then, a team of medical researchers and engineers from across the university community has met monthly to brainstorm ideas and begin collaborating on research that will hopefully succeed where other efforts have failed. "There is no better institution in the world than Johns Hopkins to see this initiative through," says Cameron, who serves on the project's executive committee. "Hopkins has broad expertise spanning clinical cardiology and surgery, biomedical engineering, and research in biological and physical sciences, plus a spirit of cooperation among disciplines that is unique among universities." Currently, only one totally artificial heart is approved by the federal government for use in patients in the United States, but it has proved to be effective for only up to 18 months. In August, a French company, Carmat, implanted its second artificial heart, made from polyurethane and natural materials derived from bovine heart tissues, in a patient. (Its first recipient died 75 days after surgery.) Tens of thousands of people are diagnosed annually with conditions that would benefit from new hearts, but because of a shortage of viable organs, only 2,000 to 2,500 transplants take place each year. More than 4,100 patients are currently on the national heart transplant waiting list. Like former Vice President Dick Cheney, many of them use a mechanical left ventricle assist device, or LVAD, as a bridge until a transplant organ can be found. Unfortunately, many die waiting. "There is just not a sufficient number of organs to transplant everybody with significant heart disease who is eligible," says Gordon Tomaselli, a professor of medicine and chief of Cardiology at the School of Medicine, who has been involved in the initiative from its start. "This is the medical problem that we face, so we engaged the folks in Engineering and at APL to think about how we can, in a very multidisciplinary fashion, attack the various components of this problem. It's not just a single problem; it's a collection of problems, and many of them are engineering-related." "It's a very difficult challenge," agrees Schlesinger. "It's a materials problem, fluid, mechanical, energy, medical. It's got so many different components. The question is, Which organization can bring together the array of expertise to address such a problem? I think, therein, Hopkins has a unique position." Joe Katz is playing with a fabricated aorta in his second-floor office in Homewood's Latrobe Hall. Unfortunately, it's broken, sheared off at the left subclavian artery. "I have a lot of nervous energy, so I ended up breaking it, to the delight of everyone else in the room," he says sarcastically. This is not a normal aorta, however. There's an exaggerated bulge off its left side—a major aneurism. "If this person doesn't get it treated and operated on, he's not going to live very long," he quips. Katz admits he's a newcomer to the mysteries of the cardiovascular system. He's a mechanical engineer, a specialist in fluid mechanics who has made a name for himself by employing high-tech instruments to take measurements in a variety of fluid systems, from the ocean to the laboratory, with unprecedented accuracy. He's accustomed to testing turbines, propellers, jet engines—not blood flow. "I'm a pump guy," says Katz matter-of-factly. But a permanent artificial heart is the pump problem to end all pump problems. When then Dean of Engineering Nick Jones asked Katz to spearhead the engineering side of the Hopkins Heart Initiative, he signed on immediately. In the last 18 months, Katz has set out on a journey to turn himself into a cardiovascular expert of sorts. He's picked the brains of colleagues in Engineering, met with Hopkins cardiologists, and sat in on open- heart surgeries. He's also spoken with patients hooked up to ventricle assist devices, asking them about their experiences. He found that while LVAD technology has improved in recent years, the devices still have their share of problems: Power packs can be bulky and uncomfortable for patients to carry about, the site where the power line enters the body is prone to infection, and up to 60 percent of the patients who receive them have to be re-operated on to control post-implantation bleeding. But one of the biggest problems with LVADs, as well as with existing artificial hearts, is that they can damage the blood. Through shear stress, delicate platelets—whose function is to stop bleeding in normal situations—can become "activated," causing thrombosis or clots, which can lead to stroke or heart attack. It's the reason why patients require comprehensive anti-coagulation medication, which can have problematic side effects as well. Red blood cells can also be damaged by the high shear stresses caused by pumps and leach hemoglobin, causing more problems. So for engineers, physicians, and others working on the project, the mantra has become "Do not damage the blood." "It's fundamental to the whole point," says Marty Devaney, a senior administrative manager in the Whiting School's Department of Mechanical Engineering, who's coordinating research efforts between Engineering, Medicine, and APL. "If we create an item that damages the blood, we're no better than any system out there right now, and we want to make sure we take into account the actual mechanism that does damage to the blood and limit that in our designs." And while researchers have known that artificial pumps can corrupt the blood, they haven't pinpointed where in the devices the harm occurs. There was no existing data. So Katz and postdoc Jacopo Biasetti designed a "flow loop" to see if they could record the damage being done to platelets. Working with Thomas Kickler, a professor of pathology and director of Hematology and Coagulation Laboratories at the School of Medicine, they were able to "light up" activated platelets with a fluorescent material and record the results on video. "We got some very interesting results," says Biasetti, who is, for now, the lone full-time employee working on the heart initiative. "Our aim in the next couple of months is to have an entire LVAD in our flow loop and visualize platelet activation and protein cleavage in real time on a real pump." The university has signed nondisclosure agreements with two private manufacturers, ReliantHeart and Berlin Heart, to test their LVADs in experiments, with funding coming from NIH grants. The goal is to physically witness and record where the damage occurs—basic research that will help the Hopkins team in its own designs, says Biasetti, who's coordinating efforts between three labs—those of Katz, Kickler, and radiologist Assaf Gilad, where researchers will image in a similar system a blood protein called Von Willebrand factor, vital to platelet function, that can also be damaged. "The idea is to come up with a format that should have less shear stress," says Kickler, an authority on hematology and blood coagulation. "What we'll need to do is help the engineers test whether their hypotheses are correct. Using the photo-activatable dyes in the system, the engineers can take hundreds of thousands of photographs and analyze how much of the activation of platelets is occurring and correlate that with shear stress. If we see less activation, that means there is less shear stress, and that would be an improvement." Kickler and Katz, who together have more than a half-century at the university, have been energized by the new collaboration. "I've been here 27 years, and for 26 years I've had no collaboration with anyone in the medical school," says Katz.

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