Trial of the Heart

It's just before 2 p.m. on a Tuesday in August, and Doug Bergman and his sister are waiting patiently in his room on the cardiology floor of the Minneapolis Heart Institute. There's a copy of Elie Wiesel's Night on the table by his bed. For a man about to have a needle stuck into his heart ten times, Bergman is remarkably calm.

Bergman, who lives 240 miles away in Rochert, Minnesota, has been in Minneapolis since the previous Saturday. He's taking part in ACT34-CMI, a clinical trial designed to test whether injection of autologous CD34+ cells directly into the myocardium will reduce the number of anginal episodes suffered by patients with refractory chronic myocardial ischemia. The needle a cardiologist will push into his heart muscle may contain some of his CD34+ cells, or it may not: This is a randomized, placebo-controlled, Phase II study.

The only complication so far was a fair amount of bleeding last night, thanks to the warfarin Bergman takes because he has a history ofblood clots in his legs. The bleeding wouldn't stop, so he was admitted to the hospital. But that's passed now.

An orderly comes to bring him down to the cardiac catheterization lab. He's out in the hallway before a nurse realizes no one has signed his paperwork. Once that's taken care of, it's time to go."Good luck, little brother," Bergman's sister Jo Ann Wilber tells him."This is it. It's going to work."

Bergman, a truck mechanic, has what clinicians call a strong family history of heart disease. His brother had his first heart attack at age 40, and later died of heart disease. Bergman has had diabetes since 1996. That year, he underwent triple cardiac bypass surgery. He did fairly well until 2001, when increasing episodes of angina led him to have a stent placed. That held him until 2004, when the angina returned. That's when his cardiologist in Fargo, North Dakota, Edmund Fiksinski, suggested he visit a clinic in Minneapolis for patients who had exhausted surgical and angioplasty options. (Cardiologist Tim Henry, who started the clinic, had wanted to call it the"No Option" Clinic. Realizing the potential for backfire, he named it OPTIMIST, for Options in Myocardial Ischemia Syndrome Treatment.)

Henry had Bergman enroll in a randomized study that tested injection of naked DNA transfer of the gene encoding VEGF in patients like him, based on early work by Douglas Losordo of St. Elizabeth's Medical Center in Boston. The VEGF study is still blinded, but Bergman is convinced he received placebo."There was no improvement at all," he says. Henry's partner Jay Traverse, another investigator in the CD34+ trial, says it might not have mattered which arm he was in."We were so naive, thinking we could inject the gene for a single protein like VEGF and have an effect," he says, citing more recent microarray data suggesting that between 600 and 1,000 genes in ischemic regions are upregulated and downregulated.

Bergman hasn't been able to work in years, and his chest pain keeps him from even doing chores around his house. He's on a daily regimen of blood pressure medications including beta-blockers, and insulin injections. When Henry brought up the possibility of enrolling in the CD34 trial last November, Bergman checked it out with Fiksinski."Dr. F. told me none of it is Frankenstein-related," he says."It's not far-out stuff. It's pretty close to being approved."

More than 10 years ago, researchers isolated endothelial progenitor cells from the ranks of CD34+ cells derived from bone marrow or mobilized to the peripheral blood. This provided a rationale for the idea that CD34+ cells could induce angiogenesis. Human CD34+ cells have been shown to induce angiogenesis and improve cardiac function in a rat model of myocardial ischemia, and CD31+ cells, the pig analog of CD34+ cells, have been shown to do the same in that species. The Phase II trial Bergman is enrolled in follows a successful Phase I trial of the method in humans, using direct injection following catheterization because it can precisely target areas of ischemia.

The day before his catheterization, Bergman had been hooked up to an apheresis machine through two thin plastic tubes inserted in his groin. By the time the day was over, his blood had circulated through the machine four times. With each whirring of the small pumps situated in and around the machine (the size of a small refrigerator), it extracted a fraction of Bergman's white blood cells, filtering and leaking them slowly into a square plastic bag just a foot from his head that imperceptibly filled with a brownish-red fluid.

Bergman could spare the white cells. On the morning of the cell collection, his white cell count was 36,800 per microliter of blood, more than four times his normal. He had been receiving a shot of the white cell booster Neupogen, a granulocyte colony-stimulating factor, every day for five days, since Saturday.

Bergman knows this is a double-blinded, placebo-controlled trial with three arms, so the color-coded syringe that comes back from the lab tomorrow afternoon may be filled with saline instead of cells. Even if he gets the cells, he'll receive only 10 million or 50 million, a fraction of what the machine is sucking out of him today.

Either way, he kept a watchful eye on the bag as it fills, thinking of the growers in his home state."A farmer would not take his eyes off the payload," he says."Today, we harvest. Tomorrow, we plant crops."

Henry says that Bergman is typical of patients in the OPTIMIST Clinic."His cardiac function is a little bit abnormal, but pretty much normal," he says, pointing as one of Bergman's angiograms flashes across a computer screen."His coronaries are closed, but there are lots of collaterals," he says, referring to the arteries created in the coronary circulation to make up for blockages and allow blood flow to otherwise unsupplied areas."If he lies there, he's fine. The problem is, if he does anything, he gets angina." All of that, says Henry, makes Bergman a poster child for the CD34 trial."He's young, he's got good collaterals. He's never going to die from this."

Henry and Traverse have more than 1,000 regular patients in their clinic, and through referrals from across the US Midwest, have in the recent past seen about 1,100 patients with myocardial infarctions. Last month, they saw 50. That puts them in a good position to recruit patients for the CD34 trial and others. There have been other trials of various conditions and cell types. Many of the early ones took place in Germany, which Traverse notes were mostly of patients with high ejection fractions (approximately 50% - 55%) who aren't really at risk for congestive heart failure. Several trials are now underway in the United States, including Columbia University, the University of Pittsburgh, and the Texas Heart Institute in Houston. It's a small band of investigators, many of whom are somehow involved in each other's trials. Much excitement surrounds cardiac stem cell trials, but that excitement has been tempered by mixed results in early studies.

Bergman is the seventh patient Henry and Traverse have recruited for the CD34 trial. Eventually, 150 will take part in the multicenter study."How many people would fit the criteria for this treatment? No one knows the answer very well," says Henry."We'll look at the whole spectrum, from any ischemia you can't fix, up to class 3 or 4 reversible defects."

The technology necessary for the CD34 trial, it turns out, already existed. Baxter International developed the Isolex Cell Selection System about 15 years ago, and in 1998 the company added a step that fishes out CD34+ cells using a peptide from the capture antibody."When we started that work, we focused the effort on oncology," says Norbert Riedel, chief scientific officer at Baxter."Chemotherapy depletes the bone marrow, and we first mobilize, collect, and select patients' CD34+ cells to repopulate it."

The company was also"constantly scouting the universe for new business opportunities," says Riedel, and came across the work of Losordo and his colleagues, Jeffrey Isner and Takayuki Asahara. They had looked into other clinical areas, including renal failure, but in cardiology they saw an opportunity to work with that team using an already-approved device whose processes were mostly FDA-approved, with the only new area being implantation of cells into the heart."You could argue why didn't we do this in chronic renal failure?" says Riedel."In interventional cardiology, these are established protocols. I'm not excluding using these cells in other areas, maybe renal failure, but we need a way of proving that they are as versatile as we think they can be in regenerating tissue that is one or another way injured."

They went forward with the Phase I trial, led by Losordo, and based on those results, the Phase II trial that Bergman enrolled in was approved. Despite the positive results so far, Baxter, and the cardiologists taking part in the study, acknowledge that even if CD34 cells are having an effect, no one yet knows the mechanism."People say, what is the best stem cell?" Henry says."It depends on what you're treating. We're trying to grow new blood vessels, not grow a new heart. Could CD34 cells cause myogenesis? It's unlikely, but nothing is impossible."

By the time Bergman is rolled into the cath lab just before 2:30 p.m., there's a bit of a crowd on hand. This is no ordinary day in the interventional cardiology suite. Traverse, in a gown and goggles, is standing by Bergman, who is lying covered on the exam table. A cath technician, a nurse, and the usual others in the team are present, but so is Rachel Olson, the study coordinator, two Baxter representatives, and undergraduates and medical students working with Henry and Traverse. Everyone but a few people watching on monitors safely ensconced behind radiation-shielding glass is wearing heavy lead aprons.

In a corner of the room, John Yang, who works for Cordis' Biologics Delivery Systems Group, is setting up the NOGA Cardiac Navigation System, which will map out the conductivity and motility of Bergman's heart as Traverse drags a catheter tip over his myocardium. Yang travels to between 15 and 20 trials like this per month, all over the United States and in Asia.

Bergman gets some Versed and Fentanyl for sedation, and at about 2:50 p.m., Traverse places a catheter in Bergman's groin and begins threading it up through his femoral artery. There's a slight delay as Bergman is shifted so that reference patches on the exam table are moved out of the range of the image projected on a screen in front of Traverse.

Then, everything is ready for the NOGA mapping."Can I start?" Traverse asks. Yang gives the go-ahead. Traverse begins dragging the tip of the catheter across the inside of Bergman's heart, measuring the conductivity - from -12 to -41 milliseconds - and the movement of the muscle to create an electroanatomic map that shows up in green, blue, and red pieces on the screen in front of Yang and on one hanging in front of Traverse. Green shows areas of electrical activity, and blue shows motion. Red means the myocardium has been damaged but doesn't move as it should. When the electrical map is transposed over the map of movement, Yang explains that the team is looking for the kind of area"that has voltage but maybe doesn't move as well."

"So, the LAO view is downstairs?" Traverse calls out, referring to the left anterior oblique view's appearance at the bottom of the screen. Yang says yes."Can you flip-flop me now?" The screen changes."Do that spot again," Yang says."I'm trying," Traverse responds, having trouble getting a reading.

At about 3:20, Traverse walks over to Yang's computer to see what areas he's missed, so he can clean up the image. The unmapped areas appear as black holes in the multicolored image on Yang's screen. As Traverse returns and finds unmapped areas with the catheter tip, he comes across one spot on Bergman's high anterior wall."When we hit it, we get ventricular tachycardia," a spasm of activity that suggests the area is irritable."It shouldn't be a player," says Traverse, thinking back to what Bergman's two-dimensional echocardiogram had shown. The 3-D NOGA, however, reveals a much more nuanced view.

Still lightly sedated, Bergman moves his head and hands a bit, and after being asked to hold still, is given a touch more Versed to deepen the sedation. Sometime after 3 p.m., John Mendiola arrives with a cooler containing a vial of the fluid to be injected. As if to warn everyone from getting too close to the liquid gold inside, someone urges him to tell the story of a local television reporter who came to witness a similar trial. Standing with a vial of cells on camera, the reporter dropped them. A catastrophe was averted, but no one is taking any chances today.

With targets now identified by the NOGA, Traverse and Henry, who has joined the party, wait until just after 4 p.m. as Mendiola and the technician prepare the vial for injection, loading its contents into pipettes that attach to the end of the multiuse catheter now in Bergman's heart. The two stare intently at the screens in front of them."Let's do that one," Henry says."Your voltage is 14, your loop is at 6," Yang calls out. The cardiologists take a pass; the voltage figure indicates electrical activity, but the loop figure is too high, indicating too much movement to guarantee stability of the needle. They want the loop number to be between 3 and 4; below 4, they're 90% confident that the needle is staying where they want it to. Researchers estimate that on a successful injection, some 3% to 6% of the cells (if indeed cells are being injected into Bergman's heart) will stay in the injection site.

A moment later, they find such a spot."Your voltage is 10.4, the loop is 3.4," Yang says."Injecting!" says Henry, who squeezes 0.2 cc of the fluid through the needle into Bergman's heart muscle over a period of 30 seconds."PVC!" Traverse blurts out, referring to the presence of a premature ventricular contraction, or ectopic heartbeat, that suggests they've irritated the myocardium with their injection - and hit their mark.

Traverse and Henry now sound a bit like batters waiting for a perfect pitch, letting others go by but frustrated by a pitcher with poor control. There are enough good pitches, however."Volt 13, loop is 7," calls out Yang as Traverse hits a pedal by his foot at another suboptimal injection site."13.6 voltage, loop 5," then"13 volt, loop 4.9," Yang continues."It's the hiccups that are doing it," says Henry, referring to some extra heartbeats. Then, there's a"volt 13.3, loop 3.0.""That's number 3," says Henry, as he injects another 0.2 cc.

Potential injection sites come and go, with Yang steadily calling out voltages and loop figures."I wanted that one so bad, John," Henry says wistfully as an area he knows is poorly perfused comes up without a good site. But then, the ninth injection is perfect."Right in the middle of the zone," Henry says, elated, as he turns to his audience."If you were Irish like Jay and throwing darts, that would be a bulls-eye."

The last of the ten injections is at 4:22 p.m. Yang says Traverse and Henry saw PVCs in eight or nine of them, a good indicator."Hey Dougie, we're done," says Henry, leaning over Bergman."Everything looked great."

Over the next year, Bergman will have five follow-up visits; he'll undergo an exercise stress test and cardiac magnetic resonance imaging, among others. His only complication so far was a groin infection, not uncommon after catheterization, and treated successfully with antibiotics. A month after the procedure, he says he's had no real changes, but has noticed slightly fewer anginal episodes than before - something he's not sure to attribute to the procedure, or less activity, or something else entirely. For now, he will just wait."I hope for the best," he says."I hope it grows some new arteries. I don't expect to be a young guy again, but I don't like to be slowed down."

Correction (posted October 9): When originally posted, this story incorrectly stated that Doug Bergman was connected to an Isolex machine in his hospital room for apheresis. He was connected to an apheresis machine. The Isolex Cell Selection System is used in the lab to sort CD34+ cells from other white blood cells. The Scientist regrets the error.