Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  CHAPTER 6

  Discovery: Myocardial Protection

  and Blood Cardioplegia

  The path of scientific discovery is unpredictable, to say the least. Who’d have thought that one man’s comments at a conference would change the trajectory of my entire career? It focused my spotlight upon not protecting the laurels of yesterday, but toward exploring tomorrow.

  Yet for this fresh round of research, our goal was the same: to uncover a better way to protect the heart during surgery.

  At UCLA, we were enjoying success with the intermittent aortic clamping as described in the last chapter, and outside institutions experienced similar achievements. But the methods were admittedly cumbersome, involving extra steps that many surgeons did not want to do. I recognized that our procedures could be greatly improved if we found a safe method that allowed us to extend the clamping period while still avoiding heart damage, as Rodewald had suggested was possible by using cardioplegic solutions.

  The possibility of using cardioplegia in this procedure was not new to me, but I had my doubts about its safety. Cardioplegia is the administering of a chemical solution to arrest (stop) the heart’s beating during surgery, as well as a way to protect the heart when its natural blood supply is stopped. This approach was introduced in 1955 by Denis Melrose in England.3 But significant clinical problems had accompanied its use. Sometimes it worked and sometimes it did not, and people died due to ventricle damage. This technique was largely abandoned in the early 1960s.

  At AATS, Rodewald presented better cardioplegia results than I’d heard previously. He was among the first to report that you can do cardioplegia safely.4

  Progress had been made elsewhere as well. Recent studies showed that the cardiac damage following use of the Melrose solution3 was caused by its exceedingly high concentrations of chemicals (including potassium and citrate and other concentrated particles) in the cardioplegia solution that was mixed with blood.5, 6 In the United States, Gay and Ebert used a crystalloid (water-based) solution6 and showed that using more reasonable concentrations of potassium offset problems with cardioplegia solutions. Finding a safe way to use potassium would be valuable: potassium causes the heart to stop in a flaccid state — non-contracting and limp — making it easier for us to operate. Gay and Ebert also avoided citrate, which could lower the heart’s calcium levels dangerously and cause cell injury, and they excluded chemical components that drew fluid from cells, causing them to shrink.

  These new studies overturned the devastating problems in the Melrose solution — and the interest in cardioplegia was suddenly reborn.

  First Bench to Bedside Test: Unexpected Outcome

  My experience at the AATS meeting sent my team in a new direction, with a new goal: to learn how to safely stop the heart with a cardioplegia solution. There would be many steps along the way, as the pathways for each of our discoveries would build upon the one that came before it. It would be a three-year quest filled with exhilarating successes — and terrifying failures.

  Though the Rodewald and the Gay and Ebert crystalloid (water-based) solutions were much safer than the Melrose approach, they were not perfect, as both still had issues with impaired post-operative heart performance. But we followed their lead and designed our own crystalloid cardioplegic solution. Our experimental studies showed it to be successful following one hour of aortic clamping to stop the heart, yielding results that matched the clinical effectiveness reported by Dr. Rodewald at the AATS meeting. Despite this, we still didn’t use this cardioplegic approach in patients because we observed some heart cell membrane damage. Further studies were needed.

  My team and I continued trying new mixtures to solve this dilemma. Eventually, we found a way to better protect cardiac membranes by adding lidocaine (a local anesthetic) to the solution. This development gave us the confidence to go to the operating room and begin to use our newly developed cardioplegia solution in patients.

  That’s when the unexpected happened.

  Nobody had ever given this solution that we created to cardiac surgical patients. My first case involved doing a coronary artery bypass procedure on a man who had traveled to UCLA from Santa Barbara, since we were recognized as performing operations more safely than in other centers.

  Everything was prepared. I arrived, scrubbed in, and began the procedure with the rest of the operating team. I inserted a needle into the aorta, and after it was clamped, the cardioplegic solution was delivered by my perfusionist, Chuck Dyson. Chucky (as I called him) reported that all was well.

  The heart immediately stopped — as it was supposed to. Then we placed grafts beyond the obstructions in the coronary arteries, and the procedure went flawlessly. We finished, and took off the aortic clamp to wait for the heart to spontaneously start beating again.

  But the heart did not restart.

  We waited. And waited.

  “Something’s wrong.”

  The heart was sitting there, limp and still, as if we’d been doing an autopsy.

  It retained the flaccidity it had had while we were working on it. Unmoving. Meanwhile, my heart was racing.

  “How long has it been?” I asked.

  Chucky consulted the clock. “Five minutes.”

  Everyone was trading looks. Finally, they all turned to me. But I didn’t understand this any better than they did. What had happened??

  Again I turned to Chucky. “How long now?”

  “Ten minutes.”

  My apprehension was growing exponentially! I went from bedside to bench to bedside, and the second bedside wasn’t working. I was confronted with somebody who may never recover. That’s all that was going through my mind.

  “Fifteen minutes.”

  I stood there, powerless, in front of that limp heart. I pled with God to come down and help me. Aloud, I pled, “Please, Chucky, make it beat.”

  But Chucky had no answers either. I was filled with anguish. I’d just caused the most serious kind of cardiac damage possible.

  Did my experimental solution cause a fatality in my patient?

  Mercifully, thankfully, 23 minutes later, the heart simply started beating. Those were the longest 23 minutes of my life. The patient made an uneventful and full recovery.

  It was me, the surgeon, who was damaged.

  Eventually, we recognized that the prolonged arrest was due to our initial use of lidocaine having been delivered in concentrations that were too high, but we didn’t know this at the time. Currently, new studies use lidocaine at lower doses, more successfully.7

  I was discouraged, but still believed we could do better. Though we’d had successes in the lab, it was definitely not time to present this protocol to our staff surgeons or publish it. As mentioned, our surgeons and many others in the U.S. and around the world were quite satisfied utilizing the periodic clamping protocols that we had developed and described at AATS.

  We returned to the lab.

  Though we had successfully shown that our cardioplegic solution could extend aortic clamping for over an hour, our studies still revealed damage to the heart’s membrane. We could measure leaking enzymes from the heart to reveal the degree of this tissue damage, and we reviewed other surgeons’ experiences and found they too were finding enzyme leaks during the first 24 to 48 hours.8

  Surgeons carefully watch their patients for six to ten weeks after surgery. But you really need a lengthier follow-up to know if there are any late consequences. It was eventually recognized that there is a progressive mortality after the heart is injured during the operation: the ten-year death rate following damage that causes a substantial enzyme leak is four times higher than when no injury occurred.9

  This striking statistic means that just because someone with significant enzyme leaks gets out of the hospital, it doesn’t mean they are out of the woods. Not at all.

  The Road to New Thinking

  Medical advancements do not start in the laboratory. They come about by observing, then asking the right questions… and mos
t importantly, by listening.

  The best part of going to conferences is not presenting my own findings, but listening to the observations of others. Such attention is essential to the investigative mind. Do not be confined to the small tribe of researchers at your institution. Reach out to others around the country and the world. Observe the problems they encounter, and their solutions. This principle of travel and listen is a mantra that I teach my students. The “seeds” for growth is to have humility, for retaining this quality will permit your open mind to continually search for new knowledge.

  I presented our periodic or intermittent aortic clamping (every 15 minutes) approach at the AATS conference. The technique became a formidable arrow in the quiver of tools available to cardiac surgeons and many began to use it. That led to my first career invitation to be a guest speaker, extended by Dr. John Kirklin (Figure 1) at the University of Alabama, to talk about the work we had been doing. I was honored. Dr. Kirklin was one of the most prominent and influential cardiac surgeons in the world.

  Figure 1: Dr. John Kirklin

  I was escorted to a large classroom holding between 50 and 100 students and colleagues. Dr. Kirklin walked in with his clipboard, taking notes as I spoke about all the various things we’d been doing at UCLA. Then, as is typical in these kinds of presentations, he would challenge whether something I presented would work, and I would use my data to explain my logic.

  Dr. Kirklin possessed incredible curiosity. He would hold tenaciously onto the past until a new idea came to light. Once he trusted that the new development was well-founded, he would abandon tradition and move on.

  Dr. Kirklin asked probing questions, and in turn, explained that he had used our short intervals of periodic clamping during coronary bypass procedures, though not during aortic and mitral valve replacement. In the aortic and mitral valve surgeries, his team instead used deep hypothermia (placing ice around the heart) to markedly cool the ventricle and lower its energy demands, which allowed for longer periods of aortic clamping. Though I was answering his inquiries about my research, it was actually I who was gaining powerful insights as I listened to his observations.

  This heightened when Dr. Kirklin invited me to join him afterward on his rounds in the intensive care unit. It was here that he reported an observation to me that would inspire my experimental and clinical studies for the next 25 years.

  We stopped by one patient who just had a coronary artery bypass graft to improve blood flow to the heart using the mammary artery (from behind the chest wall) as the bypass graft. Kirklin explained, “This surgery went very well. It was an excellent graft and I was quite satisfied. Except I noticed something very odd during the operation.”

  “What was that?” I asked, my curiosity piqued.

  “I had my hand on the heart as I completed the graft and took the clip off the artery to return blood flow to the heart. Suddenly the heart went rigid. I literally could feel this. It was soft before and abruptly stiffened.”

  “Really,” I wondered aloud in surprise.

  “There’s even more to it than that. The heart’s initial rigid condition then softened over time, back to normal.”

  Very odd indeed! His observation indicated that the muscle developed this firm condition immediately after its blood supply was restored. This reflow process is known as reperfusion. This rigidity was temporary because the stiff muscle progressively softened.

  “What do you think happened?” he asked.

  I considered his intriguing question. My response was shaped by my previous studies on the use of cardioplegic solutions to protect the heart. A theory was forming….

  “I wonder, could this phenomenon relate to how the heart deals with the calcium in the blood flow being restored to it? It is possible, after a period of being without a blood supply — that it cannot handle the return of normal calcium in the blood for some reason and reacts. Almost like a charley horse.”

  Dr. Kirklin nodded at this new consideration. Of course, he wouldn’t be convinced until it was proven. All he said was, “That is interesting. Very interesting.”

  I thought so as well. Metabolizing calcium is critically important for both contraction and how the heart uses energy. Could some change occur in a muscle while it is without blood… that compromises the muscle’s natural ability to self-correct, such that a hazard is created by simply returning ordinary blood after ischemia (when the heart receives no blood flow)? If so, it would pose a serious challenge to any cardioplegia solution that might be used. This needed to be studied.

  And I knew just the team to do it.

  Changing Winds

  As is the nature of research, a new observation created a new question. My course shifted again.

  I had gone to Alabama to share my research and returned with new insights. Dr. Kirklin’s astute clinical observation led me to the world of reperfusion — where blood is returned (called reflow) to the heart after a period during which it received none. My previous fascination with blood flow had now become my passageway into this new realm.

  So I returned to UCLA with the stage now set for a series of challenging and paired investigations: step one was learn how to safely stop the heart for prolonged periods of time. Step two was to safely bring it back afterward.

  The Stone Heart

  Up until this time, the accepted wisdom was simply to restore the normal blood supply. No one had ever researched controlling the conditions and composition of reperfusion blood. It was uncharted territory.

  I realized that these detrimental effects may not be limited only to those portions of the heart supplied by the bypass graft artery — but that such damage may also develop throughout the heart. Proof came from a report by Denton Cooley, a superb cardiac surgeon from Houston, who observed that his patients’ entire inner ventricular wall became irreversibly rigid, following 30 minutes of aortic clamping during valve replacement.10

  “Irreversible” meant the patients had died. He termed this lethal outcome “the stone heart.”

  Cooley’s experience added an intriguing piece to the puzzle: while the damage observed by Kirklin was temporary, Cooley’s was permanent. Presumably, this was due to longer periods of lack of blood and insufficient heart protection. While Kirklin had used 15-minute periods of ischemia (no blood to the heart), Cooley had used 30 minutes of ischemia. Those additional minutes somehow shifted a temporary injury that recovers… into lethal damage.

  You can imagine the frustration and powerlessness of a surgeon, who after successfully repairing malfunctioning valves or remedying defects that have existed since birth, is confronted with a drastically flawed heart upon restoring blood flow. The family can only join him in lamenting that the damaged heart was injured more than helped, despite his technical success.

  The age-old riddle of cardiac surgery.

  Calcium Connection

  Driven to understand these observations, I initially explored my hypothesis that calcium was one of the culprits: that managing “normal” levels of calcium in the blood returning to the heart was somehow too much for the ischemic heart to handle.

  This much I knew: an injured heart does not efficiently move the calcium back and forth between the inside and outside of the cell. Calcium sometimes gets into the cell and does not come out. If there’s too much calcium within the cell, the heart has a sluggish contraction, doesn’t relax well, and can’t use oxygen properly.

  But how do we lower the level of calcium when the heart can’t do it?

  I turned to a protocol used by blood banks. To avoid blood clotting during storage, calcium concentrations are lowered by adding acid citrate dextrose (ACD), which binds the calcium.

  We would use ACD to lower the calcium concentration.

  But there was a problem. We would want to use only enough ACD to lower the calcium the right amount… but we also knew the blood will clot if it doesn’t contain enough ACD. Our two parameters might be working against one another. We solved this by adding an additional ingredie
nt — heparin, an anticoagulant. This substituted for the need for ACD to prevent clotting — and freed us to lower calcium by just varying ACD concentrations.

  So then the question was: how much ACD is needed?

  A significant issue, since we couldn’t make calcium measurements in the lab. So we chose to use a practical test of sequentially adding ACD, 1 cc at a time. We’d know the right amount after we observed how the heart’s performance recovered.

  We added 1 cc of ACD, then 2 cc, and 3 cc, and so on to the reflow blood until we found that 9 cc of ACD was the effective amount.

  The results were terrific!

  My hypothesis was based on our research that the heart underwent metabolic and chemical changes during ischemia (when no blood was going to the heart). We believed these changes could be remedied by the way in which blood supply was restored. Our results proved this to be true and led us to devise what we called controlled reperfusion. Rather than reintroduce a normal blood supply after the heart had been ischemic (stopped without blood), we added citrate phosphorus dextrose (CPD) — a variant of ACD — to control the calcium concentration of the returning blood. It successfully avoided the injured, rigid hearts that were previously observed by both Kirklin and Cooley!

  Looking Deeper

  We now had a way to safely reintroduce blood flow to the heart after surgery. Each of us on the team felt a real sense of pride.

  Yet there was more to do.

  I now wanted to re-look at how standard methods of heart protection may not prevent damage from occurring during the operation, and uncover ways to bring such an injured heart back to normal.

  Topical cooling (hypothermia) is commonly used, and was the first method we studied. This technique, first introduced by Norman Shumway at Stanford University, showed that cooling the heart limits damage when the heart’s blood supply is stopped, by slowing metabolism and reducing its need for oxygen.11 Though it was broadly accepted, we wanted to find out if this topical cooling method avoided problems from occurring in heart function.