Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  We tested this approach in 77 consecutive patients. The results were again outstanding!17

  The other UCLA cardiac surgeons were thrilled as we all came to a profound conclusion: “This will change the thinking about myocardial protection all over the world.”

  Welcome Acceptance

  Our final step was to report these findings to the American Association of Thoracic Surgery. This was 1978, three years after I had presented to AATS when Rodewald from Germany marched up to the podium after me and opened my eyes to a new possibility for cardioplegia. It was time to present the results of what had sent me soaring in a new direction.

  There was great sense of anticipation at the conference, as the immense potential of what we had found was evident to those that scheduled the order of presentations. They scheduled our paper to be presented first. I was pleased by this, though I wouldn’t do the presentation myself. My name would be on the paper and that was all I needed. I was already known in the cardiac community. This was an opportunity for the research fellow to present it, as he had done the experimental and clinical analyses. In this case, David Follette.

  I sat in the audience as David went up to the podium. He gave a wonderful presentation. The crowd of over 4,000 surgeons listened keenly. They recognized the impact that this discovery would yield.17

  It would allow surgeons to no longer feel compelled to rush through procedures, in order to limit the time a heart would be stopped when its blood supply is interrupted. Cardiac surgery would be transformed as patients would survive and recover more fully than ever before. We had made operations much safer for them (and 40 years later… this innovation continues to be used).

  This achievement was profoundly fulfilling. The ability to give to others, as encouraged by my mother and grandmother, now seemed to be within my grasp. Helping to ensure the success of cardiac surgery was a goal that exceeded what I’d imagined when my studies had begun several years earlier. Yet I also knew we still needed to await further testing before the full magnitude of this concept could be confirmed.

  CHAPTER 7

  Improvement:

  Cardioplegia Saves Lives

  After observing and studying why the heart was more hurt than helped during open-heart surgery, we reported our new findings at the American Association of Thoracic Surgery. We described a successful approach that solved this universal problem.

  You’d think I would be on top of the world.

  The fact is, I nearly lost my job.

  Although cardiac surgeons throughout the national and international community became early adopters of blood cardioplegia — because they now could have a safe and much longer operating environment in which to do their delicate work — the reality is that cardiac surgeons do not always have the final word in how a procedure will be performed. The patients’ primary heart doctors are cardiologists, who act as gatekeepers. They refer patients and frequently try to prescribe the operative procedures.

  I learned of this barrier initially at UCLA, where the cardiologists discarded our new treatment. They were angry and frustrated, and called for a joint meeting (of their group and the cardiac surgeons) to accuse the surgeons of experimenting on their patients.

  They claimed our new blood cardioplegia procedure was “radical,” and responsible for the “closures” of coronary artery bypass grafts that were occurring four months after the bypass procedures were performed. Yet they presented no evidence that blood cardioplegia had anything to do with these closures.

  I responded to their questions by comparing our past use of intermittent ischemia (the periodic aortic clamping that we had also created) with the newly developed blood cardioplegia, and also provided the experimental results demonstrating its safety after four hours of aortic clamping, to justify why our clinical results with patients had improved with this new technique.

  My presentation fell on deaf ears. The cardiologists were adamant about accounting for why some grafts closed four months after the operation. They could not find the cause, and they had to blame someone. That someone was us — me, in particular.

  I wondered if I might be dismissed from the faculty. But a counterbalance also existed, as my fellow surgeons at UCLA embraced the new methodology, and it was being adopted by many surgeons that practiced outside our institution.

  I was confounded and annoyed by the actions of my accusers. Who rejects proven science? Why would anyone dismiss procedures that have substantively shown improvement in the care of their patients? These were questions I could not yet answer. Unfortunately, it would not be the last time I would ask them.

  I decided to spend no additional time on this conundrum. We had more work to do on our blood cardioplegia solution. My credo was that research is never completed. Instead, the process involves posing the next question that each discovery generates. The excitement and beauty of this pattern unfolds to involve observation, new questioning, and then testing to learn and grow. This unending thirst for understanding is what unveils the magnificence of science.

  Our cardioplegia protocol was a major breakthrough — but could it be made better? I believed it could. I decided to explore how to magnify its usefulness by simplifying our method of its delivery.

  Temperature — A Matter of Degree(s)

  Aside from focusing upon how to use cardioplegia, I realized we needed to determine the best temperature at which to deliver it during different times of the surgical procedure.

  A ripe area to explore. Hypothermia was a well-established added strategy to cool the heart when the aorta is clamped. Cooling lowers the heart’s need for energy (metabolism), which falls 50% for every ten-degree drop in temperature. Conversely, the heartbeat is strengthened following warm cardioplegia delivery.18

  To me, this observation suggested a balance might exist, whereby the blood cardioplegia solution could be delivered at different temperatures during the various phases of the procedure: starting the operation, throughout the procedure, and during reperfusion after it is complete.

  With this in mind, I posed the following possibility to my team at one of our weekly meetings: “What if there wasn’t just one best temperature to use with these solutions? Nature itself is commonly composed of blends, the most obvious being its alternating temperatures of day and night. What if it is better to use different temperatures during different parts of the operation?”

  A radical idea, but the team was excited by how the world of free thinking had entered our research effort.

  Testing with the Damaged Heart

  While many of our studies began with a normal heart, we understood that normal hearts are uncommon in patients that need cardiac operations. Instead, their hearts are weakened and vulnerable to damage — they barely limp along. Protecting such damaged hearts was our mission, so we needed to do studies with a new experimental approach that mimicked the kinds of hearts we typically encountered.

  To create such damage, we subjected pigs to 45 minutes of aortic clamping at normal temperature without any cardiac protection. It worked, as there was only 25% of ventricular performance recovery after the aortic clamp was removed. This mirrored the very vulnerable hearts that we cardiac surgeons commonly face.

  Those hearts must then confront the added challenge of undergoing the prolonged period of aortic clamping (no blood supply) that cardiac surgeons will require to surgically correct the difficult underlying cardiac defect. These are termed high-risk patients, since recovery of such injured hearts may be precarious.

  We simulated this experimentally by subjecting the animals having damaged hearts (due to their having undergone 45 minutes of aortic clamping without any effort to protect the heart) — to two more hours of aortic clamping with myocardial protection. This time frame mirrored the 120 minutes that we needed to correct a severe underlying heart problem. During this interval, we applied each of our new cardioplegic protection methods, as described below:

  We started by delivering a five-minute introduction of warm blood cardiople
gia, intending to improve nourishment to the damaged heart before its undergoing prolonged aortic clamping. Then gave four minutes of cold blood cardioplegia to limit damage during aortic clamping, repeating this cold solution every 20 minutes over two hours. Finally, a warm reperfusion was delivered just before removing the aortic clamp.

  The outcomes were astonishing: cardiac performance in these vulnerable already damaged hearts returned to 85% of normal!19 Just imagine: these high-risk hearts initially could only show 25% recovery. Yet our dramatically improved results (85% recovery) meant use of our cardioplegia method allowed us to “repair the heart metabolically,” while at the same time to surgically “correct it mechanically.”

  Recognizing that the heart ended up better than when it started — made us appreciate that we had developed a very powerful new tool to prevent injury.

  Oxygen Metabolism — Making Better Even Better

  Understandably, we were thrilled. Our cardioplegia protocol by itself helped “an already hurt heart get better.” When we informed Dr. Maloney, he was astounded and elated as well.

  As always, our result — no matter how good it may be — does not only provide an answer. It also provides the next question, so we naturally asked, “Could its effectiveness be even further enhanced?”

  This question brought me back to recognizing that the pursuit of scientific growth is often tightly linked to returning to the basic sciences. That attitude is usually absent in freshman medical school students. They often grow impatient with studying basic anatomy, biochemistry, and physiology. They want to “study sick patients, just like a real doctor.” They don’t understand that physicians must know these basics — especially about oxygen metabolism — to help them make effective decisions.

  Yet little did I realize as a medical student, how these lessons about oxygen could subsequently help me learn to better protect a patient’s heart from sustaining damage.

  One magical gift of the laboratory environment is exposure to the ongoing thoughts of our research fellows. Their inquisitiveness inspires much of our progress. In 1986, Harold Lazar, a resident surgical fellow from the University of Michigan, spent two years in our research laboratory. He only studied damage after aortic clamping, and never did any cardioplegia research.

  But Harold was very observant. He knew the healthy heart extracts about 75% of the oxygen from the blood that nourishes it. As a result, the blood that exits the heart (called venous blood) has a very dark blue color because nearly all of the oxygen (that gives its red color) is extracted in the healthy heart.

  He came into my office one day with a troubled look on his face.

  “What is it, Harold?” I asked.

  “I have a question. Could the heart’s metabolism be altered after we have stopped the blood flow?”

  A curious question indeed. “What did you see, Harold?”

  “When I’ve been restarting blood flow to the hearts of our sick animals after their own blood supply had been clamped off, I noticed the venous blood exiting the heart is red — rather than the dark blue it should be.”

  My eyes lit up. It was a striking observation.

  “Red? So you’re thinking that after they’ve had their blood supply removed for an interval of time… when it’s restarted, these hearts are for some reason less able to extract oxygen from blood?”

  “Exactly,” Harold confirmed. “If they can’t extract oxygen, maybe there’s some damage to the mitochondria [tiny cellular structures] where energy metabolism takes place.”

  I took a moment to lean back in my chair, taking in this prospect.

  Then Harold added, “I was also thinking — we know the amino acid glutamate is a key ingredient for the heart to metabolize oxygen. What if we simply add some glutamate into the reperfusion solution to see what happens?”

  That suggestion triggered my memories of basic science classes in med school, and the roles that amino acids glutamate and aspartate played in heart metabolism.

  I encouraged Harold, “If you can figure out how much glutamate to give it, please start the new experiment. I look forward to seeing the outcomes.”

  Harold did just that. He added glutamate into the blood at the end of the clamping period, and to his absolute delight, observed that the venous blood exiting the heart, which was previously red, now became blue! This meant the heart markedly enhanced its capacity to metabolize oxygen — most likely due to better mitochondria metabolism — and its performance substantially improved.20

  Upon hearing his report, I said, “Harold, that is really amazing. How much glutamate did you add?”

  “10.83 grams,” he told me.

  I was impressed with his precision in dose selection. “How did you arrive at exactly 10.83 grams?”

  Harold hesitated a moment before answering. “Actually, I was searching the literature and the only thing I could find was that 10.83 grams was given to children with diarrhea.”

  “Diarrhea?”

  “Yes. That was it.”

  “So Harold, you’re essentially telling me it was a total shot in the dark.”

  “You could say that.”

  I began to laugh. Diarrhea was a pretty far cry from our exploring impaired cardiac metabolism. Sometimes discoveries are stumbled upon in the most unexpected ways.

  Actually, I didn’t know how unexpected until just last year — 31 years after Harold did this experiment.

  I ran into Harold at an AATS meeting in Seattle, where I mentioned I was including his story in my memoir.

  His amused response was, “Gerry, would you like to know how I really arrived at that figure of 10.83 grams of glutamate?”

  “I thought I knew. It was a component of the diarrhea formula.”

  “No,” Harold admitted. “I just told you that because it sounded more plausible than how it really occurred.”

  I stared at him. “The diarrhea story sounded more plausible than the method you really used? Harold… how did you arrive at that number?”

  “I phoned up several Chinese restaurants and asked how much monosodium glutamate they put in their noodles. Then I used that information to calculate the amount of pure glutamate to use in our formula. And it worked — experimentally and in patients — and has continued to work for last 31 years.”

  Harold’s prior story of determining glutamate dosage from studies of infants with diarrhea had been amusing. But his real explanation was hilarious. Who knew Chinese cooking would play such an historic role in cardiac medicine! I’m well aware that great revelations can come out of unusual events, but this had to be a first, strange as it was.

  Harold then mischievously added, “By the way, my deep reasoning behind the Chinese restaurant query was that if it didn’t make the customers sick and they came back for more, it would work on our patients.”

  I looked at Harold a moment and had to laugh out loud again. I’ve always encouraged my students to think outside the box and to maintain a good sense of humor about their work. Now 31 years later, I was reminded that one of the beauties of having students is their taking on the playful humor of their teacher, and then letting it fully blossom.

  Despite how it came about, Harold’s calculated addition of glutamate was successful, and his contribution proved to be a superb benefit that substantially improved recovery of injured hearts after their blood supply had been clamped off.

  Although excellent results followed the use of glutamate in our cardioplegia solutions, we must always search for newer ways to make it even better. Sometimes a symphony already sounds great, but adding an extra violin or viola may make the music even sweeter.

  Eliot Rosenkranz, a subsequent research fellow from UCLA that worked with me, wondered if the damaged heart was also deficient in aspartate, the other amino acid that plays a vital role in heart metabolism. He added this to the formula and found excellent results.19 This enriched blood cardioplegic solution, with glutamate and aspartate, has been used ever since as a component of how we protect the heart during
cardiac surgery.

  The real beauty of our enhanced formula was that the cardiac surgeon now had the key tools to accomplish a dual purpose. First, we can fix the heart mechanically by the technical excellence of the operative procedure. Second, we can repair it metabolically by using our cardioplegia approach to help it at the cellular level. This combination allows us to provide the complete package of “repair and protection” to our patients.

  A lesson became clear: basic biochemistry learned in medical school should not be dismissed. It furnishes the fundamental knowledge that is needed to uncover the critical stepping stones for solving clinical problems.

  All Together Now….

  I have enormous respect for the interdependency within a treatment protocol. Despite this vital interaction, I’m often asked by cardiac surgeons: “Of your entire cardioplegia protocol, which techniques have you found to be the most important?”

  No doubt the inquiry was posed in the hopes they could select one or two items that are so highly effective that they could forgo the rest, giving them a shortcut to simplify their operations. But my answer always will compare cardioplegic techniques to a symphony. If the conductor were asked to identify the most important instrument, he would say it is the one that is not playing correctly. The harmony of an orchestra exists during myocardial protection, and intertwining the cardioplegic blood solution, its temperature, and route of delivery will define a critical and useful strategy for optimizing heart protection during cardiac procedures. All the instruments playing together are what make the music so powerful.

  Going Backward is a Vital Step Forward

  Our cardioplegia formulations became widely used, patients’ lives were saved, and their post-operative health improved. While delighted, I also recognized our formulations can only fully protect the heart — if they are distributed to all the needy areas within it. Impediments to that existed, and they needed to be overcome.