Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  While this certainly saved many who would have otherwise perished, there was a problem. It was causing a massive amount of lung congestion, a condition that was called Vietnam Wet Lung. As a result, they were losing these young healthy soldiers.

  Upon learning of this, my natural response was, “Why did this happen? We have to figure this out.” I got involved.

  I attended a meeting organized by the military in Washington, DC, with representatives invited from major academic institutions to consider this problem. A surgeon from New Orleans suggested that the lung swelling happened because the major lung veins went into spasm for some reason and narrowed, and thus prevented good drainage of blood through those veins, resulting in congestion. Sounded interesting.

  To determine if this diagnosis was accurate, I went back to Dayton to see if I could reproduce this in animals. I caused the animals to go into shock by removing a lot of blood, and then measured their lung vein pressures. To perform the measurement, I developed a curved cannula (a tube with a handle) (Figure 3) through which we passed a catheter into a tiny hole in the heart’s left atrium, and then passed it into the lung (pulmonary) vein.

  Yet the pressures we measured in the veins remained normal. With this, we determined there was no such problem with the major lung veins, so the theory proposed by the surgeon from New Orleans was wrong.

  (The cause of Vietnam Wet Lung was later found to be the use of water or saline transfusions. This differs from what occurs when blood transfusions are used to replace what had been lost, since the infused blood remains in the arteries and veins. By contrast, the water or saline solutions will leave the tiny capillary blood vessels and enter the tissues, and this leakage is most evident in the lungs. The medics were giving massive saline infusions that saved lives, but inadvertently caused the lung congestion that followed.)

  Figure 3: Upper example is tubing device (cannula) for entering lung veins from left atrium. Lower example shows similar device for entering the coronary veins from right atrium.

  While I was able to evaluate the validity of this surgeon’s theory, I also realized something else: the device I’d created that was used on the left side of the heart — might also prove to be a valuable tool on the right side of the heart — and permit us to study ways to better protect the heart during cardiac surgery. After all, if the catheter could be easily placed into heart’s left atrium and into a vein within the lung — why couldn’t it be passed into the right atrium (via a tiny incision) and just as easily be passed into the coronary veins — to take blood samples and help us study heart metabolism?” (Figure 4)

  We tried this… and it worked!

  This major forward step would later permit advances in understanding the heart’s metabolism during both health and disease. What I couldn’t yet foresee was this cannula technology would also allow another important discovery to emerge while I was at UCLA ten years later — one that would help finally unfold the mystery of why damage to the inner shell of the heart caused death after open-heart surgery. This would play a vital role in allowing surgeons to safeguard the heart during cardiac operations. This will be described in the next chapter.

  Figure 4: Tubing device shown passing from right atrium to coronary veins (called coronary sinus)

  One of the most valuable things I learned during my medical training is that you never know where that next inspiration will come from. After all, sometimes it can be as simple as an apple falling off a tree (as when Newton discovered gravity). You just need curiosity and an open mind. This cannula — initially used to show that the prior theory about the lungs was wrong — would later be used on the other side of the heart and contribute to the success of cardiac operations.

  Setting New Course

  By the end of my military service, I had charted a clear path for my professional career.

  I would be a clinical surgeon and a researcher. This pathway differs from that of the typical researcher, who never sees the problem firsthand in patients. Yet this vital combination allows the laboratory to act as the launchpad toward finding initial answers, and simultaneously sets the stage for subsequent development of treatments that I and others could use to resolve these issues.

  I entered the world of translational surgical research as I adopted a “bedside to bench to bedside” approach with key steps. First, I had to recognize a persistent problem occurring with patients (bedside), then perform research in the lab (the bench) to develop a solution, followed by testing it in my patients (bedside again), then asking colleagues to test it with their patients. Finally, if successful, I had to teach everybody about it. This has been the game plan of my experimental / clinical explorations for over 50 years. It combines my passions for investigation, discovery, and practice.

  Accordingly, after fulfilling my military obligation in 1969, I entered the Cardiovascular Research Institute (CVRI) in San Francisco to become skilled at the rigorous process of defining a medical problem, developing a hypothesis, designing an experiment, and measuring the results… and recognizing that any failures simply point to the next step in the progression toward uncovering the answer.

  In short, CVRI would teach me how to be a researcher.

  CHAPTER 4

  Becoming an Investigator

  Recognized contributors to our profession have always had heroes — accomplished individuals that are giants who show us how to build a solid foundation for growth. We never start alone. We do not win some lottery for success. Rather, our internal spirit evolves while relying upon the guidance of these prior leaders.

  These mentors provide total commitment to their new students. Julius Comroe, the head of the Cardiovascular Research Institute, was one of these. He was an outstanding scholar and teacher who essentially gave up his career in pulmonary research to create an institution that furnished the educational “seeds” for the development of our future leaders. His unyielding commitment was to infuse us with the fundamentals of knowledge: how to use it, and how to create it. The research fellow always had complete access to his attention. On the other hand, such access was not possible even for recognized international scientists coming to San Francisco; they could not see Dr. Comroe without a prior appointment. (Figure 1)

  Figure 1: My CVRI mentors, Julius Comroe and Julien Hoffman. Their teaching set the tone for how I taught my students.

  I’ll never forget his class on teaching us how to review medical literature — information published in journals and texts dedicated to the field of medicine. He asked me to comment on an article published in 1935 about blood pressure responses and the carotid artery. I was given 45 minutes to read this two-page paper, which reached its conclusions from studying only two experimental subjects. Dr. Comroe demanded to know what my editorial decision would be on this brief manuscript that offered only limited investigative data and unsupported concepts.

  Of course, I rejected this paper due to its deficient research, essentially no statistics, and imprecise questioning of what was known. Dr. Comroe gracefully accepted my surgical point of view… then informed me that my decision was not shared by the Nobel Committee, who had bestowed their prize onto Corneille Heymans for this unique and scholarly description of the carotid sinus reflex… a fundamental contribution toward understanding normal physiology.

  It was an important lesson for me: listen, learn, but do not be so eager to evaluate and dismiss. Rather, consider and grow from what you are shown and go forward from there.

  This, as did many lessons gleaned from those who came before me, influenced my professional evolution and helped further set the stage for how I would conduct my future research.

  My principal guide at CVRI was Dr. Julien I.E. Hoffman, a cardiologist, physiologist (specialist in functions of all parts of the body), and thoughtful mentor. He taught me how to respond to data I collected through research: how to look at it, find the new questions stimulated by the data, and answer those questions in a way that provided reasons for everything I was asserting.

>   “You don’t simply report your observations — you must understand the biological mechanism underlying the study, and also appreciate the study’s limitations.”

  A methodologist in his research, Julien wanted us to make sure our investigative techniques were done properly. He insisted on absolute certainty about our findings before any report was finalized.

  Though demanding, he was patient with surgeons without exception. He welcomed your ability to ask the questions he had not thought of, rather than you simply providing a solution that he already knew was true. He urged different views and evaluated each idea carefully… then would sometimes tell you with incisive, dry wit that your excellent conclusion might not actually be correct. But only after examining all the factors, would he either reject you on a solid basis, or more importantly, encourage your next step.

  Removing the “Blinders”

  While I was at CVRI, we wanted to create an experiment to finally solve the mystery that had been plaguing me and others: why were so many open-heart surgery patients not surviving, even though their operations had been done in a technically perfect way?

  Most of those patients didn’t die on the operating table, but sometime after the surgery was completed. What I consistently witnessed in the autopsy suites was that the inner shell muscle — the muscle closest to the ventricle chamber responsible for pumping blood into the body — had either died or was severely damaged. Something must have happened to it either during or after the operation, and we wanted to know what it was.

  Actually, we had to know.

  A normal assumption would be that too little blood flow had gone to the area. Typically, that would be from an inadequate blood supply to the heart due to narrowing or obstruction of the coronary arteries. But those vessels were open (not blocked) in these patients. That was not the problem.

  Adding to the puzzle was that we weren’t seeing any damage to the outer muscle of the heart. It appeared to be fine.

  So why was there inadequate blood flow — just to this inner shell muscle?

  Using Microspheres

  We began to measure the blood flow to this inner shell muscle (also called the endocardium). While we were already capable of measuring the amount of blood going to the whole heart through the arteries, never before had anyone been able to repeatedly measure the amount reaching specific regions inside the heart through the capillaries.

  Until now.

  Julien Hoffman developed a breakthrough concept of measuring blood flow with small microspheres. The microspheres were tiny man-made polymers — each just slightly larger than a red blood cell. They were to be injected into the left atrium of a laboratory animal’s heart. Because they were a shade larger than red blood cells, they would become entrapped in the heart’s capillaries — vessels so small that only a single red blood cell can barely squeeze through.

  Because these microspheres were also radioactive, we would be able to track their locations during the experimental study. We hoped to accurately measure the blood flow to this inner shell of the ventricle by counting how many microspheres had become trapped.

  This would be a huge advance — if it worked. Sorting this out became a challenging experiment. The study was carried out by me and three other surgical residents, and Julien Hoffman guided our efforts.

  The first step was to determine the distribution of flow when the heart was normal. This was equally critical to learning what happens when something goes wrong. If you don’t know what normal is — the way the heart should be — then you cannot know what has changed and cannot fix the problem.

  The experiment began.

  We injected the microspheres under ordinary conditions to establish that critical starting point. Their movement was tracked by a spectrometer, and as we had predicted, they became entrapped in the capillaries, revealing to us their flow distribution in the heart’s muscles when everything was normal. This established, for the first time, that we could measure blood flow in the inner shell (endocardium) during an experimental study.

  It was a great beginning.

  These initial results confirmed what would be our baseline: that under normal circumstances, the blood flow to both the inner shell muscle and the outer muscle were the same. But that still left us with the riddle: what changed to cause damage only to the inner shell muscle. That’s what we would look at next.

  Astounding Results

  Here’s what we knew about the heart before we started: each time it beats, the heart’s muscles contract in order to pump the blood from inside the cavity of the heart to move it out into the body. But in doing so, that compression also squeezes the arterial blood vessels within the heart’s walls — those that carry nourishment to the contracting heart muscle itself. Each squeeze restricts the amount of blood flowing through them.

  In fact, the blood only flows freely to these heart muscles when the heart relaxes between beats.

  While this was true for both the inner and outer muscles in the heart, we also knew from previous studies — that this compression on the blood vessels was greater within the inner muscle than the outer muscle.

  Could that be the clue?

  No one knew, because until now, no one had ever been able to measure any of these changes in flow within the inner muscle before.

  Yet as we continued our experiment, we learned that during heart contraction — nearly all blood flow stopped to the inner shell muscle — while the outer muscle had only minor blood flow reduction.

  This was a powerful observation, as it meant that the inner shell muscle could only receive nourishment when the heart was at rest between heartbeats — never while the heart contracted (which meant it could not be nourished one-third of the time during a heartbeat).

  No wonder this inner shell was the most vulnerable part of the heart and at risk of becoming damaged!

  We now tested further, by reducing the blood pressure to match what it would be in patients with a leaky valve in the aorta (main artery connecting to the heart) — a disease condition that open-heart surgery commonly treats. We found the blood supply to the inner shell was down dramatically in patients with this condition. This increased the vulnerability, since it got nothing while the heart was contracting.

  I reported our findings at an American College of Surgeons Forum for young investigators in San Francisco. It was a meeting where the “next generation” of leaders in research would share what they were working on in their labs. It was an electrifying place to be and I was eager to give my presentation.

  Ours was a totally new finding. Though a small study, it was the first time anyone had ever used microspheres to prove a damaged area had too little flow, despite having open arteries.1

  The audience was intrigued. Someone even posed the question, “Could these microspheres be used to measure blood flow in other organs in the body as well as the heart?”

  “Absolutely. The brain, kidney, lungs, intestines — there are all kinds of possibilities. In fact, someone is now doing this in another study at CVRI.”

  Our results were very well received. It was a wonderful experience to be the happy recipient of much positive acknowledgment and congratulations.

  But we weren’t done yet.

  I knew we only had part of the answer.

  Missing Piece

  Our findings had told us why there could be damage during an open-heart procedure. But it didn’t answer why this happened to some patients and not others. Not every patient had heart damage after surgery.

  Under what circumstances would this happen? And could we predict it?

  So I began inducing different variations on the experiment: we tried having less blood pressure pushing into the area and saw how that would reduce the blood flow. We made the heart rate too rapid — since faster beats per minute meant less time for the heart to relax and be nourished between each beat. And we increased the opposing pressure in the blood vessels leading out of the heart — since if that opposing force was too high, new blood flow can
not enter.

  We hoped we could accurately predict what the flow rate would be to the inner shell in response to these changes we made. And we did find in each of these cases that the blood flow did reduce to the inner shell. But it wasn’t consistent. Under certain conditions, the measurement of nourishment would be adequate, while in other yet similar circumstances, it would not. We couldn’t directly relate it to the changes we made in the blood pressures or heart rate, and we didn’t know why.

  Perplexed, I showed our results to my maestro, Julien Hoffman. He looked over everything very carefully, and then asked us this question: “Have you considered factoring in for demand?”

  What a remarkable insight.

  The “demand” is how much oxygen the heart needs from the blood. Whether an area is being adequately nourished or is being damaged — will be based on how much blood supply it is receiving — compared to what it needs for the tasks it is doing. If an area had a very high requirement for nourishment, you would have a problem even with what normally would be a higher flow level because it still may not be enough.

  This would be the missing piece of the puzzle!

  It came back again to the issue of independence versus interdependence.

  We had been looking at one part: the supply. But we couldn’t tell if that blood supply was truly adequate or not, because we weren’t looking at the demand. Once we began to factor in the demand that the heart muscle would have for oxygen, we suddenly could bring everything together — and were able to predict when there would be inadequate blood flow to the inner shell muscle.