Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  Topical ice was placed around the heart in our animal test subject after we stopped its blood supply by clamping the aorta for 60 minutes. But recovery of the heart was impaired after taking the clamp off: ventricular performance returned to only 60% of normal.

  Certainly hypothermia was helpful, but its protection was incomplete, since the 60% functional recovery confirmed that an injury was still happening.

  Our next step — was to add one variation as we repeated this experiment.

  Instead of simply removing the clamp at 60 minutes, we delivered blood containing CPD for the first five minutes of reperfusion before returning normal blood flow. We then measured heart performance 30 minutes later.

  The result was startling — as there was 85% recovery of function! So on top of demonstrating a safer way to reintroduce the blood supply — this study of reperfusion also showed an improved performance of a heart that we knew had sustained an injury while its blood supply had been stopped.

  Suffice it to say, we were all extremely pleased!

  Yet we also knew we had only opened the door. We weren’t finished.

  I believed the problem couldn’t just be calcium — it had to relate to other changes as well. Nature is seldom disruptive in only one way. So our next steps were to search out and understand other reasons for the heart injury that occurs when there is normal reflow after a period of no blood supply.

  Second Problem — Lactic Acid

  We also knew that tissues without a blood supply, including the heart, always produce lactic acid that causes acidosis. This was not a new finding, as high concentrations of lactic acid were known to develop in muscles of marathon runners as they “hit the wall.” So we decided to test a new reperfusion solution that only contained a buffer to raise pH and counteract this acidosis that harms the heart cells. The buffer called THAM was selected because it had the unique ability to enter the cell, and treat the inside and the outside of the injured heart cells.

  As with the calcium study, this buffered reperfusion was delivered for five minutes and then the aortic clamp was removed. The recovery of function was 80%, revealing yet another new alternative reperfusion strategy.

  Logic Doesn’t Always Work

  We were thrilled. I looked at the other researchers and stated, “Well, if we got 85% with reducing calcium and 80% with raising pH — we have it nailed. We put them together and we will have discovered the triumphant answer!”

  The next logical step was to blend the two strategies. I fully anticipated that such a mixture would return heart function to 100%. So my cardiac surgery research fellow, David Follette, did exactly that. He used them both together and what did he find?

  Only 40% recovery.

  These results were even worse than when normal blood was given for reperfusion.

  Extremely disappointed, I declared to David, “You must have done something wrong. This has to work. Go do it again.”

  Wanting my theory to be right, I blamed the investigator for not doing the studies properly. My mistake became immediately apparent.

  David tested it 5 more times and got 40% every time.

  There was no escaping the truth. I had violated a central principle to good leadership: give credit, take blame. I was trying to pass fault onto another, when this limitation rested with me. As I have long said, when a study doesn’t work, there are only two possible reasons — either it is not done right, or the idea is wrong.

  “Clearly, I don’t understand this,” I was forced to admit. I thought for a second. “There is someone we need to see.”

  Convinced the issue still had to do with abnormal calcium, I felt this someone to see was Glenn Langer — a preeminent cardiac physiologist at UCLA and known worldwide as “Mr. Calcium,” due to his extensive research in the dynamics of how it functions in the heart. Nobody in the world knew more about calcium.

  Our team visited Glenn Langer at his office, where he listened to everything we reported. Acutely aware of the role that calcium played in causing reperfusion damage, Glenn took particular note of our describing the rigid heart that occurred immediately after reperfusing it with normal blood. He concluded this reflected a temporary contracture (a hardening of muscles that can lead to rigidity) — due to the heart’s inability to remove excessive calcium from within the muscle cells.

  Yet curiously, he could not explain why our results worsened when we combined our two successful strategies of reducing calcium and raising pH in the blood we reflowed into the heart.

  I pondered that paradox as we returned to our labs. There had to be an answer! I asked David, “Tell me exactly what you observed when you started the reperfusion with our combined solution.”

  “It was really quite something. As soon as I began reflowing the blood, the heart fibrillated (developing a completely inefficient rhythm) very vigorously.”

  I sat down and considered this. “I know the problem. The real issue is this fibrillation. It’s strangulating the blood supply.”

  Remembering that Gay and Ebert used potassium in their studies of cardioplegia, I told David, “We have to stop the fibrillation. Let’s try adding only potassium to the reflow.”

  David was enthused by the idea. He added potassium alone to the blood — and got 70% recovery. Definitely a step in the right direction!

  Encouraged, I suggested, “Now let’s add that to the other components of our blood cardioplegia reperfusion solution.”

  David tried the delivery of a combination of low calcium, higher pH, and potassium solution — after 60 minutes of having the heart stopped (receiving no blood flow), using only hypothermia for protection. Would this new solution work better?

  It did. There was 100% recovery.

  This remarkable result was tested again many times, and each duplicated the 100% recovery. We were ecstatic! We’d solved the reperfusion problem. We helped an injured heart recover through our goal of creating a new approach — controlled reperfusion!

  Right for the Wrong Reasons

  Everyone on the team was thrilled. Jim Maloney was delighted. This was a huge achievement. While I could have simply been celebrating this success along with the rest of them, one question remained completely unresolved:

  How was it possible, before we added the potassium, that we observed powerful ventricular fibrillation — at a time when blood calcium was low?

  So why should this question be haunting me? Because logically, we shouldn’t have had powerfully fibrillating hearts when there is low calcium, as this prevents the muscle from squeezing strongly. Heart contraction should have been reduced, not increased.

  This dilemma shines a light upon the beauty of research. There is never a single answer, but rather, each finding leads to the excitement to ask the new questions, whose answers will unfold along the learning pathway.

  I continued searching for this seemingly unattainable answer, and eventually found a German physiologist named Piper12 who discovered that calcium lurches into the injured cell and the muscle as blood is restored to an ischemic heart — causing hyper-contracture (overly contracted beyond the normal range) — much like what Cooley reported seeing with the stone heart after he removed the aortic clamp.

  Suddenly I realized the “vigorous fibrillation” problem within the heart that David described — was in reality an example of cardiac hyper-contracture. The fibrillation might actually have been fairly low, but the heart muscle cells were being injured as calcium entered them — and the rapid twitching movement was camouflaging the underlying heart’s rigidity. The charley horse observed by Kirklin now became lethal to the whole heart.

  Interestingly, despite misjudging what the powerful fibrillation was telling us… we had added potassium. This was the correct decision, as its use left the heart flaccid, and prevented calcium from entering the heart cells.

  It’s one of those peculiar aspects of science: sometimes you arrive at the right conclusion for the wrong reasons.

  But that wasn’t important now. We had a bl
ood composition that took a damaged heart showing only a 60% recovery with standard methods (topical hypothermia) and could now give it 100% recovery!

  No doubt about it. What we had found was inspiring.

  Two Types of People

  This successful discovery illustrates my belief, and my approach to research, which I learned from my “bible” of investigation, An Introduction to the Study of Experimental Medicine, written in 1865 by Claude Bernard, a French physician, physiologist, and creative thinker.13 He described the two kinds of people that exist in the scientific world: the observers and the experimenters.

  The observers are the spectators who witness and record what is occurring, like the astronomers studying the stars. They observe nature as it happens.

  The experimenters are those who start with a bias or theory for what is happening, create the needed conditions to test their position, and then do a study to see whether their prediction is valid.

  Interestingly, when you perform that study, you must become an observer again — as nature provides the answer. Only then can the experimenter learn if their hypothesis is correct. This pattern of moving from an observer to experimenter and back to observer guides the researcher throughout his or her lifetime.

  Science is served by both types of people. But difficulties can arise when someone is no longer an observer or a participant, but becomes a traditionalist who believes something can be only a certain way. Often it’s because that is the way it has long been accepted, or it simply suits what makes sense to them. If they stubbornly hold on to that position, they’ll always “succeed” in making their view the right one. They end up going nowhere, as their path is against nature. They want their own answer… rather than letting nature show hers.

  Instead, a scientist must start with the idea that fueled their curiosity. But their theory must be tested, as we did when we simply combined the lowering of calcium and the raising of the pH. We found our premise didn’t work. If I’d held fast onto our theory and kept trying to prove it true, we never would have moved beyond it to find the answer we did.

  Science provided me with the answer, not my opinions.

  Timing is Everything — Prevention or Treatment?

  Creating our blood reperfusion solution seemed to be a great accomplishment. Persistence, hard work, and expansive thinking led to creating a solution that could reverse the injury that had been occurring during heart surgeries.

  That got me thinking again. I wondered — if we can reverse the injury after the surgery — could we prevent those injuries from happening in the first place?

  An epiphany can strike at the oddest time. Even finding a long-sought answer (like blood reperfusion) can usher in a new launching point for ideas.

  Up until then, only a water-based (crystalloid) cardioplegia solution had been given to help protect the heart during surgery. …But what about administering a blood cardioplegic solution as the operation started — similar to what we had developed for reperfusion — but instead now give this solution as the operation is to begin?

  Birth of “Blood Cardioplegia”

  Of course, our proposal to also use a controlled reperfusate at the beginning of the surgery had to be tested.

  But before we would experiment with starting our blood cardioplegia as the operation began, I wanted to make sure we would be maximizing the usefulness of the solution. I started with a fundamental question: “Is only one dose of cardioplegia solution needed during surgery?” A single dose was the customary method at the time… but I had a good reason to speculate there might be a better approach.

  When I had first returned to UCLA to join the faculty in 1971, Dr. Maloney’s lab was also being used to study heart transplantation. Dr. Colin Bayliss, a research fellow from Canada, was conducting studies that showed a donor heart could be stopped with a cardioplegia solution before it was removed from the donor’s body and stored cold (to lower metabolism) for up to 24 hours — before being placed into the recipient’s body. The heart function was excellent after it was transplanted.

  Dr. Bayliss concluded that he had discovered the ideal cardioplegic solution! Then something rather baffling occurred.

  He tried this cardioplegic solution in a simulated cardiac operation in which he clamped the aorta for just 3 hours (versus the 24 hours without blood required for transplantation). This approach also differed in that the heart was not removed (as it is during transplantation). The result?

  The three-hour heart could not recover.

  You might expect the response to be better than with a transplant, since there is no trauma of removal from the body. Yet the substantially impaired heart function repeatedly occurred, making it impossible to consider using this cardioplegia solution in patients. Something was happening in the living heart that made the cardioplegia less effective.

  I now believed that solving this riddle could help us improve our ability to protect the heart.

  The sharing of ideas forms the foundation of research. Each Monday morning, I met with two or three of my research fellows, and Dr. Maloney when he was in town. I proposed my theory at one of these brainstorming sessions.

  “It seems the difference between the successful heart function in a transplanted heart — and the failure during simulated surgery — means that the cardioplegia solution was somehow no longer present in the living subject’s heart.”

  My research fellows looked puzzled. One spoke up: “With all due respect, we close the aorta before injecting the cardioplegia solution, so there is no incoming blood flow to wash it out of the living heart.”

  I responded, “That makes perfect sense, and is what everyone believes. But what if that’s not correct?”

  Again, puzzled looks.

  I explained, “Obviously, the cardioplegic solution stays in the removed heart that is headed for transplant. But in the heart that stays in the body during open-heart surgery — could there be tiny vessels within the pericardium (the tissue sac immediately surrounding the heart), that could wash out our cardioplegic solution — despite the absence of any blood flow coming in through the coronary artery?”

  Silence now blanketed our meeting room, as my usually animated colleagues let this theory sink in.

  Fortunately, the tools to test this concept were in our hands. We designed a study using microspheres.

  We experimentally mimicked open-heart surgery by stopping blood flow to the heart by clamping the aorta — and then injected microspheres into the body circulation via the heart-lung machine. This meant that any microsphere that reached the heart would have to come from collateral blood vessels in the pericardium.

  As it turned out, they did reach the heart. The observed flow rate of 3 ml/minute was adequate enough to wash away any cardioplegic solutions!14

  We had uncovered something previously unknown (a cardioplegic solution would be constantly washed out of a heart) — that would impact how to deliver cardioplegic solutions to patients.

  This led to our next study, built upon the simple principle: if it’s gone, let’s replace it.

  Once is Good — More is Very Good

  We could not avoid this flow that can wash away any cardioplegia solution, so we developed a plan to intermittently replenish it — to preserve its protective actions. We asked, “Would that be effective? And how often should the dose be repeated?”

  We clamped the aorta for 60 minutes to simulate conditions during an aortic or mitral valve replacement. These studies were conducted by Roy Nelson, a cardiac resident surgeon from New York University who came to work with me for two years.15 One group of test subjects received a standard, single dose, crystalloid (water-based) cardioplegic solution… while the other received repeated doses every 20 minutes.

  Single-dose delivery led to a moderate decrease in heart function.

  But the multi-dose cardioplegia resulted in completely normal function.

  This was an extraordinary development that had clear implications for our patients!

 
It pointed out the problems with single-dose delivery, and opened the door to establishing a new, multi-dose protocol that may avoid the perplexing heart injuries that can still accompany technically perfect operations.

  Though we wouldn’t know it then, these findings became the seminal investigations for using multi-dose cardioplegia during open-heart surgery.

  Blood is Thicker (and Way Better) than Water

  We now knew our multi-dose method of delivering conventional crystalloid cardioplegic solutions was superior to the standard single dose. But we needed to take the next step: could our blood cardioplegia replace these water-based solutions in operations on our patients?

  This seemed like a natural approach, since our bodies have blood running through their vessels, not water. Plus, excellent results had followed our giving a blood cardioplegia reperfusion solution after a prolonged period of ischemia. The question now was: would such superb recovery take place if this solution is delivered throughout the period of aortic clamping? Could it better prevent the heart from being injured?

  A powerful test was needed, since this was a new concept, and if successful, would create a revolutionary shift in treating patients when the aorta is clamped during open-heart surgery.

  An extended surgery was simulated by using four hours of aortic clamping with multi-doses of our blood cardioplegia solution. This four-hour length would account for the time needed for even the most prolonged operations.

  But would it work?

  In a nutshell, the results were spectacular.16

  In fact, the outcomes mirrored those found in hearts that are simply left on the heart-lung machine and allowed to continue beating for four hours without aortic clamping. The findings were enthralling, because heart normality was preserved!

  The Big Test

  It was now time to take our discovery from “bench to bedside” by seeing how these new protocols worked on our patients.

  The agenda was straightforward. There would be three protective phases during an operation. First, cardioplegia is introduced when we clamp the aorta. Second, there are maintenance doses every 20 minutes during clamping. Third, controlled reperfusion is administered before returning the body’s own blood flow.