Fritiof was identifying the basic ultrastructure essential for cell metabolism, using an extremely high-powered (electron) microscope. This differed from many other histologists that viewed the basic cardiac structure with regular microscopes. He was delving deeper than most, looking at the structures responsible for the biochemical reactions that were the keystones of life. He was able to look at the causes of cell metabolism within the mitochondria. It was a perfect fit with our work.
The blend between what Fritiof could analyze, and what we saw clinically, was remarkable. One day he showed us ultrastructure images of where the amino acids are used in the heart tissues.
“Really?” I marveled at the images.
“Yes, that’s where the amino acids sit. Why the strong interest? ”
I replied, “Because part of our cardioplegia formulation includes giving the amino acids glutamate and aspartate to help the heart metabolize oxygen.”
Fritiof was literally showing me where the glutamate and aspartate work. He provided visual and other documentation of what we were doing. It was phenomenal.
Furthermore, and to everyone’s surprise, Fritiof discovered something quite startling and important to our work: he believed that the conventional and accepted testing methods to determine muscle tissue being dead were flawed.28
His pictures showed that the traditional testing technique itself caused the mitochondria to be destroyed. These vital structures were found to be entirely normal when his method of tissue preparation was used.28 It took a world-renowned electron microscopist to explain this to us. A cohesive team took form, as he worked on the histology (structural) and we worked on the muscle (functional).
A terrific collaboration.
Most importantly, beyond finding that the technique of preparing conventional staining methods themselves can produce mitochondrial disruption, Fritiof discovered that the mitochondria were normal after prolonged ischemia — a finding previously thought to be impossible. Yet such normality indeed existed. Simply stated, a look was worth a thousand words — and their normalcy was fully evident after viewing the images on his slides.
Consequently, if the mitochondria are normal — they can produce energy after a heart attack — which verifies there is continuing life within a damaged region! This landmark finding became the foundation behind our search to discover if the injured portion could recover its function. We were excited to move forward.
Turning Surviving into Reviving
Our next and most vital step was correlating Fritiof’s findings with our study that aimed to recover this heart region’s function (its ability to contract). His pioneering methods would document what was happening in the heart structure, while we looked at its performance, much like Julien Hoffman and I were able to do when we used microspheres to verify blood flow inside the heart.
If we were successful, this unequivocal evidence would show that standard beliefs are wrong… a persuasive finding that might open the door to a whole new way to approach treating heart attacks.
We were acting as rebels and renegades, dissenters, and heretics. But we would not be stopped. Unless the science stopped us.
In our experiments, we would obstruct a large branch of the anterior descending artery (which supplies the front of the ventricle and septum) for time intervals that ranged from 40 minutes… to two hours… to four hours and beyond. Our intent was to use controlled reperfusion, as described in the cardioplegia chapters, and determine if the heart could remain alive. Until this time, no other experimental study had ever shown that myocardial cells could survive after lengthy periods without blood flow.
Yet we knew that even this profound accomplishment would not be enough. Our journey needed to lead us further down an uncharted path. So we began a series of studies that would go far beyond showing the heart was still alive after these long periods of no blood. We would create new protocols to test if the injured muscle — previously thought to be irreversibly damaged (as by a heart attack) — could regain function.
A daunting endeavor. To accomplish it, we knew we’d need to resolve many as yet unanswered questions. For example, one fundamental issue is…
Oxygen Demand
Critical to keeping a heart alive is making sure it is sufficiently nourished. We knew the oxygen requirements of the beating heart, the fibrillating heart, and the arrested (stopped) heart. But what about a heart that has had a heart attack? What were the requirements of the bulging muscle that’s not squeezing? To our knowledge, no one had ever measured this before.
With our research fellows, Fumiyuki Okamoto and Brad Allen, we recreated a bulging segment in a working animal heart by nourishing this region with an infusion of blood containing high potassium — essentially mirroring what happens structurally during a heart attack (except this bulging region would be pink due to ongoing perfusion, instead of blue as it is during a heart attack).
What we discovered next was entirely unexpected.
The oxygen requirements of the non-contracting bulging segment were nearly as high (70%) as a fully working heart!
Fortunately, we found we could immediately lower those demands to almost negligible levels (10%), by decompressing (venting) the heart with the heart-lung machine (to mimic what is done in cardiac operations). This provided much greater protection against further damage, and venting following a heart attack became another critical component of restoring the heart.29
However, solving these oxygen needs was only one of 16 studies that we did during our four-year journey, during which we discovered piece after piece after piece of what was needed to protect and restore the muscle damaged during a heart attack.30 These many individual aspects would work together to solve a huge problem. It is much like what we had to do to solve cardioplegia and everything else that I describe in this book. It is never one simple step to resolve these critical issues. If it was, somebody else would have already solved them.
Who would pursue something like this? Only crazy “Uncle Bucky” does that.
For us, however, it was tremendously exciting. We kept finding all the hidden pieces to each wild puzzle. Once you do that, suddenly you have solved problems that were deemed unsolvable. Then you can create solutions to medical issues, whose implementation may affect massive numbers of individuals and their families.
Collaborative Components
Our 16 studies established new principles for treating heart attacks.30 The approaches crossed over between the specialties of cardiology and surgery. We were not proprietary about who did what — our goal was to define what could be done. Our new protocols would intertwine with one another, requiring an orderly choreography to implement them together. The surgeons and cardiologists involved in our tests were no longer simply doctors; they were dancers in an exquisitely orchestrated, life-saving ballet.
While understanding the importance of each of our new findings may be beyond the realm of the non-medical reader, the milestones of this voyage need to be acknowledged in this memoir. As each one was met, another challenge presented itself — until we had found all the parts to the riddle.
This is a partial list of what we uncovered:
Using the heart-lung machine together with controlled reperfusion initially expanded the window during which we could regain recovery of heart muscle from 40 minutes to two hours.
Those vital tiny mitochondria that control energy production were still intact after six hours without blood flow — and remained alive and functional after controlled reperfusion.
Lowering calcium levels in the reflow blood prevented movement of calcium into the heart attack cells, which then avoids impairing mitochondria function.
The damaged non-contracting muscle bulging from a heart attack needed 70% of the oxygen required by a normal beating heart. Yet when decompressed (vented) as during surgery, it required only 10%.
Using a gentle reperfusion pressure of near 50 mm Hg prevented the edema (swelling in tissues) that would result from higher reflow pressures.<
br />
Identified proper concentrations of high glucose (to include in the blood reflow) needed for nutrition and increased osmolarity (number of particles in blood) to avoid water accumulation in the tissue.
20 minutes of controlled reflow was required to achieve maximum recovery. (Shorter intervals achieve less functional improvement.)
Muscle injured by the closed coronary artery sustains four to five times more damage if the heart is not decompressed during medical procedures.
Decompression by venting is essential.
These new methods worked equally well in the experimental surgical operating room and the experimental catheterization lab.31
The last discovery deserves special emphasis since we found that our approaches could be used in the cardiologist’s catheterization lab or in the operating room. The common objective is to follow the new principles of how reperfusion is delivered. Typically there is a debate whether the cardiologist should do their procedure or should the surgeon perform an operation. But the reality is the heart muscle does not care how blood gets back into it. It can come through an angioplasty catheter or via a surgical graft. The shared aim of returning function to the heart attack area is the only significant goal, not territorial disputes between cardiologist and surgeon.
The New World is Finally Reached
Once we had our recipe down, it was time to begin the final set of studies. We subjected the heart to prolonged durations of no blood supply, in order to create the inevitable cell death that would result from an injury that was believed to be inescapable.
The results?
During this experimental investigative process, we found the heart was much more vibrant than its “presumed counterpart” (thought to be a dead steak) — despite several hours of ischemia (no blood flow). At every stage, Fritiof’s documenting that the heart sustained only negligible cell damage served to counter what had previously been established as Accepted Wisdom. The heart was still kicking — and could still function — thanks to our novel controlled reperfusion treatment.
We then tested our procedure in the most challenging of circumstances: when the heart muscle region experiences six hours of ischemia. If this was successful, it would more than meet the need for developing a treatment that could help a heart attack victim who had been untreated for a prolonged period.
This approach was also completely unheard of. No heart could survive six hours without nourishment… or so it was believed.
This was a critical stage for us. With all that we learned, if our methods didn’t work for such extended periods of time, their use would be limited. A great deal was at stake. We faced a powerful test of our credibility.
The validity of our approach was confirmed.
Our use of controlled reperfusion consistently made cardiac regions that had received no blood flow for six hours… recover their ability to contract!32
What’s more, Fritiof’s ultrastructure analysis confirmed what we had observed functionally: the mitochondria responsible for producing energy were not disrupted. It was amazing!
Better yet, we still didn’t know the limits to how long a heart could survive using our protocols. Might the heart survive eight hours… or ten hours… twelve hours? In a sense, we had no idea how long it would be before the heart was truly dead.
Going Public
We felt what we had established would create nothing less than a revolution in conventional thinking. It was a game-changer. We hoped our colleagues in the medical community would pay more attention to these results than they had to our prior reporting of early findings when we recovered function after two hours of an acute heart attack. In 1981, I had watched as Jake Vinten-Johansen, the research fellow conducting our study then, presented our preliminary results at the American Heart Association in a session about novel techniques. After he finished, not a single question was asked, nor any interest expressed.33
But now it was several years later and we had every reason to believe people would be excited about our newest findings. Nobody had ever before accomplished getting the muscle damaged in a heart attack to function again — let alone after six hours!34 Our team showed it could be done.
…Yet once again, to our great disappointment, this demonstration of recovery of muscle previously thought to be dead — had absolutely no impact upon the cardiology community.
They seemed wholly indifferent.
Although potentially demoralizing, I didn’t take it as a low point. I don’t function that way. As the composer Phillip Glass observed, “If you do not worry about people that do not care about you, it is the passage to freedom.”
You keep on working. The high point for me is when we find the answer, and progress is only furthered when you keep making your understanding of it better and more useful and meaningful.
The truth will eventually win….
Leaping from Theory to Practice
Even though the larger medical community ignored our initial findings, the events of one night showed me that some of my colleagues at UCLA had taken note of our research… and gave me an unexpected opportunity to turn theory into practice.
It was far after my normal UCLA office hours when a knock on my door lifted my head from my notes.
“Yes?” I called out.
“Doctor Buckberg?” a man asked in a soft voice. “I am Nobi Kawata, recently appointed clinical cardiologist in the medical center. I am sorry that I do not have an academic appointment. So I apologize if this interruption is inappropriate.”
“That’s fine, Doctor Kawata. Welcome to UCLA. How can I help you?”
“Time is short. I have a patient — a man who’s had a massive heart attack and is at great risk of dying.”
This caught my attention.
“Frankly,” Doctor Kawata added gravely, “I have nowhere else to turn.”
That got my full attention. He explained the patient had no chance given the normal procedures. His heart attack occurred 11 hours ago.
“Eleven hours?” My maximum experience up until this point was six hours. This was a big jump… and would present a powerful test of our concepts. I had never tried my procedures on any patient, let alone someone after 11 hours of ischemia.
Big jump indeed.
Dr. Kawata had heard about my research on controlled reperfusion and hoped it might work on his patient. The region undergoing damage was large, and the problem of early death was compounded by his likely developing heart failure in the long term, if he survived.
I knew we needed to try. “Please take me to meet him.”
My office was a short distance from the medical center and we rushed over. The patient was in the cardiology cath lab. I quickly accessed the situation and called the operating room.
“This is Dr. Buckberg, I have a red-line case.”
A red-line means ultra emergency. You are put ahead of anyone else into the first room available. They immediately got a message to the perfusionist on emergency call to come in while I reached the chief resident. “We have a patient with an acute infarction and need to proceed now.”
The patient was moved into the operating room and all was ready to go within 30 minutes. Everyone assembled (nurses, residents, anesthesiologists, perfusionists) knew what to do. Once we began the operation, I was able to look at the heart. Sure enough, the part affected by the heart attack was bulging and blue (no blood supply). We immediately put him on the heart-lung machine and decompressed the ventricle to shrink it down and diminish its oxygen needs.
While no one said anything, I could tell from their eyes that several were wondering just what the heck we were doing. No one had ever done anything like this before on someone 11 hours after the heart attack.
Everyone had operated on heart attack victims in cardiogenic shock, where the focus was taking care of the remote muscle to keep the person alive. But they’d never done our protocols for treating the “dead area” of the heart to restore it. In fact, I’d never discussed this with the house staff at a
ll. But I now told them we had a way of dealing with this.
So we began.
One of the first things I did after we started the heart-lung machine was to feel the heart. To my delight, the damaged region of the heart was soft.
“Thank goodness — the heart is still soft. The calcium hasn’t flooded into the muscle cells and impacted mitochondrial function.” It was hopeful news.
We first performed the necessary grafts to open the narrowed arteries to supply blood to the functioning remote muscles — the part of the heart keeping the man alive. We wanted to give it the best possible protection.
Then we did a graft on the artery feeding the heart attack region. We infused our cardioplegia solution into the damaged area (about 50 cc a minute, making sure the pressure wasn’t too high) for 20 minutes.
I utilized everything we had learned from our 16 studies. It was all coming together under the most demanding of circumstances.
All of this went perfectly. The operating team followed each instruction, even if they didn’t always know the purpose of each task. Then came the moment of truth. Time to remove the clamp and restore the blood supply.
We did. The whole heart started beating, including the heart attack region.
I was ecstatic. “You see it. That’s incredible!”
Everybody was thrilled and stunned. What we had done was unheard of. It was truly extraordinary. Yet based upon our experimental background, it was predictable!
Dr. Kawata’s patient recovered in smooth fashion, and imaging studies verified the region undergoing acute myocardial infarction had indeed regained normal function. Dr. Kawata was very excited and grateful.
I was delighted that UCLA cardiologists would now know what we could do clinically with patients. I expected streams of patients to soon come our way.
But that did not happen. Old mindsets are hard to change. We had very few patients referred to us even after we had shown what we could do and the much greater prospects that we offered, for both short- and long-term recovery.
Still, I was undaunted. For someone forging a new trail over the course of several years, this experience showed we had reached the next mountaintop.
Solving the Mysteries of Heart Disease Page 14