With this, we finally solved the baffling mystery of why a piece of the heart could die or be injured even though the coronary arteries were open and the surgery was impeccably performed. We now knew it wasn’t a matter of obstructions. It was about the balance between the blood supply going to that area and the oxygen demands.
This led to developing what became our “supply / demand ratio” — a mathematical formula that measured this relationship between blood supply and the inner shell muscle’s requirements for oxygen from the blood. We called this the DPTI/SPTI ratio (Diastolic Pressure Time Index / Systolic Pressure Time Index). (Figure 2)
Figure 2: Upper part shows how blood pressures (B.P.) were used to calculate the diastolic and systolic time indexes (that measures supply and demand). Lower tracing shows coronary artery blood flow (CBF) that predominantly happens when the heart relaxes during diastole.
This would become the biggest breakthrough of our study. We took a process (blood flow to the inner shell) that was previously so complex that no one could even measure it… and translated this unique information into a formula that merely used the patient’s blood pressure and heart rate. Plugging those numbers into a formula would accurately predict if sufficient blood supply was getting into the inner shell muscle of the ventricle. An exciting and thrilling end result.
Valuable Tool to Improve Care
Our discovery opened the door for much better care during that critical period after open-heart surgery during which we had been losing so many patients. This was vital because it provided guidelines to treat damage that may follow the operation — one that impaired the heart’s ability to contract, resulting in worsening of the patient’s condition.
Now for the first time ever, any doctor, nurse, or other clinician could take a simple measurement of the patient’s blood pressure and heart rate, and put those numbers into our simple formula to determine if damage had occurred and if the blood supply to the inner shell was now adequate. If it wasn’t, they could administer the appropriate drugs to support the heart, helping it get past the injury. Simplicity replaced the sophisticated technology of measuring flow into the heart muscle.
By understanding how to deal with an imbalance between the heart’s blood supply and its need for oxygen to give it energy, we finally addressed the question I began asking at Johns Hopkins when I first observed hearts being “more hurt than healed” after surgery.
I should also note that even with our terrific and very gratifying results, Dr. Hoffman nearly drove me and the other three research fellows crazy as he came up with additional methods that he wanted us to use to confirm our findings before we published. His message was “You never say anything publicly until you’re sure of it, but once sure you are correct, don’t be afraid to say it.” It made me understand that if you are right, nobody can attack you to overturn the truth.
That was another great lesson I’ve adopted in my own work. When I know I’m right, it doesn’t matter what others say. You keep going forward, despite being faced with opposition. Truth will win.
Next Mountain Peak
Our research and hard work were well received. In fact, of the over 450 papers I’ve published, the paper describing our findings about how to use microspheres to measure flow in remote and inaccessible regions of the heart has been the most quoted article of my entire career.1
Yet as great as this advancement was, I still recognized that we were dealing with the consequences of something that must have occurred during surgery. Somehow, despite having a technically perfect operation performed, the inner shell muscle was still getting damaged in many patients. Finding the answer to this riddle became the next mountain to climb. My time at CVRI was coming to an end, so I would return to UCLA to address this challenge. My first project.
My schooling wasn’t over. I now understood that the surgical skills and scientific methods I had learned before CVRI only reflected the beginning of my education. This boy from the Bronx was now a cardiovascular researcher and surgeon, armed with the tools, passion, and ambition to try to set a worldwide course for fixing broken hearts.
Needless to say, I was excited to use everything I’d learned in trying to understand and solve this devastating complication.
CHAPTER 5
Great Expectations
After completing my fellowship at CVRI, it was my great fortune to return to UCLA and work on the faculty as an assistant professor under James Maloney, the Chief of Cardiothoracic Surgery.
I vividly remember my first day on the job. I had an immediate need to speak with Dr. Maloney, who I knew pretty well by this point. I was aware of the emphasis in academic medicine on publication. Dr. Longmire had informed me some time before of the need to publish many papers on your research, since productivity was viewed as the road to success.
But Dr. Longmire (Figure 1) was wise and advised me that, “Sometimes they count them and sometimes they weigh them. …But they never read them.”
Figure 1: My surgical teachers, James Maloney and William Longmire, who taught me how to use the operating room to ask new questions that needed innovative answers.
In other words, the focus was to publish something, but this task was rarely geared toward providing information that would improve the status of medical science. The researcher’s mandate of “Publish or Perish” made no sense to me, as I could waste a lot of time trying to play a “paper game” without meaning.
I was not willing to squander my time. There was too much valuable work that needed to be accomplished.
So on day one, I approached Dr. Maloney and said, “Jim, I know the criteria for academic success is to publish numerous abstracts and subsequent papers. But here’s something else I also know that is true: I can’t work under an obligation of needing to do something just for the sake of doing it. I need to perform research in a way that can make a real difference. I don’t want to be in a position where the measure of my success is marked by how many pages I can generate.”
It was a pretty bold statement, especially by a brand-new faculty member. But I even went a step further by adding, “If there are such requirements for publication and presentation in this department, I would have no choice but to begin looking for another position immediately.”
Dr. Maloney looked at me a long moment. “Let’s take a walk.”
He escorted me into his lab, through its range of facilities, past various staff working there.
“I hear your concerns,” he ultimately replied, “so this is how it will be.” He faced me straight on. “Here, you can work on whatever you want. I will provide the equipment and the people. I will offer my thoughts as you show me whatever you are developing. If in two years we need to have this conversation, we’ll have it then.”
That was unexpected… but music to my ears.
Of course, that conversation would never happen, then or in the future. During the next two years, I would be free to create innovative experimental research that would become translated into new methods and technologies to help patients after heart surgery.
Jim Maloney showed his faith in me that first day and put me in position to succeed at what I wanted to do.
He had a very good reason to do so.
Things were not going particularly well. As with most medical institutions, UCLA was experiencing too many injured hearts after cardiac operations. The survival of our cardiovascular program depended upon the development of new approaches to be used for protecting the heart during open-heart surgery.
This dilemma wasn’t helped by the department’s response to this problem: focusing only on the speed at which a procedure could be performed. This approach was based upon the belief that the longer the surgery, the more damage would occur in the ventricle’s inner shell. Besides being a shortsighted concept, outcomes were not helped by the fact that UCLA is a teaching hospital, meaning residents would operate while being overseen by the more veteran surgeons. They performed excellent procedures, but their inexperience meant they
required more time to do the operation.
More experienced surgeons at other (non-teaching) hospitals were faster. These prolonged operations at UCLA led to fewer referrals for open-heart surgery from cardiologists.
So the belief at UCLA was that “time was the enemy.” But I had explained to Jim Maloney that while this might be true with ordinary or conventional surgical techniques, the true problem wasn’t speed. Instead, the basic issue was how well you protected the heart during each procedure, and I was dedicated to discovering new and safer techniques that would allow for longer operations that could be done safely, and would not subject the heart to progressive damage.
This is why he provided me free reign in my research.
As already noted, I first recognized this problem of a heart “more hurt than healed” during my residency at Johns Hopkins, and this complication became a well-recognized dilemma throughout the cardiovascular community. The extensive damage to the heart’s inner shell that I observed after attending postmortem studies at UCLA was happening everywhere. But its cause baffled everyone.
Yet I was lucky, because I had a technique that might uncover the reason.
As the previous chapter described, I learned at CVRI how to measure blood flow in remote regions of the heart (including the vulnerable inner shell) and calculate the relationship between blood supply and blood demand — determining that the heart becomes damaged when demand isn’t met. Essentially, I knew what to look for, and had the tools to measure what was happening. I was eager now to embark on a detective’s path that might uncover the cause for a major worldwide problem.
Jim Maloney agreed that battling the clock was not a winning solution. He was hoping I would find one.
I was now on a mission.
Forging a New Trail
It was time to begin the work. This study would be my first opportunity to fully apply the “bedside to bench to bedside” approach that I had chosen to adopt when I entered CVRI. It includes three steps:
The first starts with observing and defining a problematic clinical event: the functional damage happening in patients’ hearts (the bedside portion) after a technically successful procedure. To gain a more complete picture, I would always consult with the other attending physicians and surgeons to learn what they were observing. Dr. Comroe at CVRI taught me that while others’ viewpoints may not always concur with mine, my understanding of a problem grows by listening to differing opinions. For example, I might see four things occurring; they might see a fifth. I needed to grasp the whole issue.
The second step is to recreate in the lab (the bench) the same disease event, and design research studies that will lead to the development of techniques that will solve the problem. Now, I did not do this alone, but am grateful for the assistance of research fellows from UCLA, as well as other universities both nationally and abroad. We are a team, and they conduct much of the study under my direction, yet they are encouraged to ask probing questions that may take us in different directions. Julien Hoffman had demonstrated the incredible value of remaining open to new ideas. Throughout my career, I was never invested in wanting to be right, but rather to find out what was right. The power of listening must triumph… and it does.
The third step involves translating a successful laboratory experience into a clinical solution to be used in patients (the bedside), and ultimately used by more and more surgeons as acceptance grows. Admittedly, this last part can be easier said than done, for even with their expressed enthusiasm for new discoveries, many physicians may still not want to use them. In medicine (and in many other endeavors), people have a tendency to do what they did yesterday. This roadblock must continually be overcome, as I would learn throughout my career.
Mission Launches
So I began my first experimental study at UCLA as a new faculty member. I had access to world-class equipment, with staff and research fellows to assist me. There was freedom to order what I needed to duplicate the microsphere measurements that I had performed at CVRI. A perfect launchpad.
Yet these tools were common to all experimental laboratories. The piece typically missing is the ingenuity to develop new ideas, then do experimental studies to test their truth, and finally to use these concepts in sick patients. Again, I was reminded of Einstein’s adage, “Imagination is more important than knowledge.” Hopefully ours would meet the challenge that we needed to face.
Our experimental subjects would be large pigs, given the similarities of their circulatory systems to our own (in fact, you may know that pig heart valves are sometimes used to replace human valves today). Fortunately, another positive attribute of UCLA was that it had the highest level of animal protection requirements. Its policies for making sure test animals were properly protected were very specific, in their being properly anesthetized and well taken care of before, during, and after experiments.
Ventricular Fibrillation
My work would start on ventricular fibrillation (VF), since purposely inducing VF in a patient was commonly used to quiet the heart so cardiac surgeons could operate more easily. It is very difficult to perform procedures on a beating heart. So a patient would typically be connected to a heart-lung machine that took over pumping oxygenated blood throughout the body — as a momentary electrical stimulus is applied to cause the heart to spontaneously fibrillate. Instead of a normal pumping motion, the heart would quiver minutely, so that it essentially does not move and cannot perform any useful cardiac action. Once begun, the heart would continue to fibrillate on its own until the procedure was complete, at which time an electrical counter shock (called defibrillation) would be applied to restart the heart’s normal rhythm.
The question I posed was: might using ventricular fibrillation during operations be connected to the heart damage we were seeing far too often?
The vast majority of cardiac surgeons didn’t believe so, because ventricular fibrillation was used routinely in many centers worldwide. But I wanted to find out for sure.
Our study began with normal hearts. We would induce spontaneous fibrillation with a momentary electrical stimulus in a heart, just as it is done during a surgical procedure. We would then let the heart fibrillate on its own for an extended period (one hour), and then restart the test subject’s heart with another electrical impulse to return it to normal function.
Our results showed excellent performance. There was no evidence of any damage to the heart, and no need for drugs to help support its capacity to contract normally.
However, one particularly interesting fact did emerge.
We already knew that blood flow distribution in a healthy beating (not fibrillating) heart is equally distributed to its inner and outer muscles — the flow ratio is 1:1.
Yet when measuring its distribution during fibrillation (by using the microsphere protocol we had developed at CVRI) — we discovered the inner muscle received 40% more blood flow than the outer muscle.
That was a significant finding since the blood flow to an area will match its oxygen demand requirements (amount of oxygen needed) when it functions normally. Our unanticipated finding revealed that when the inner muscle is fibrillating — it has a 40% higher flow need in order to have its oxygen requirements met.
This observation was especially notable because “normality” in any given circumstance is not necessarily what we anticipate (equal blood flow distribution to the inner and outer shells). Instead, our testing of fibrillating hearts demonstrated the reality, whereby more flow is needed to the inner shell in order for the heart to maintain normal performance.
This baseline information sets the standard for our analyzing for potential damage (impaired function) after open-heart procedures, where the inner muscle failed to receive the required 40% increase in blood flow.
Consistent Current = Persistent Problem
It was time to create our first experimental effort to mimic what happens during a clinical procedure (meaning one that would occur with a patient).
For this, we chan
ged from inducing fibrillation with a momentary electrical stimulus — to applying a continuous alternating current. This continuous approach was used by many cardiac surgeons — who were worried that the spontaneously fibrillating heart (from a momentary stimulus) might suddenly resume beating in the middle of a procedure. The continuous low level current ensured that this did not happen.
Our new results differed dramatically from those using a momentary electrical stimulus to cause fibrillation.
These hearts became swollen and did not beat well! Our chemical tests documented that cell enzymes had leaked, certifying there had been cellular damage. This experimental finding confirmed other recent reports that heart performance was impaired following continuous ventricular fibrillation (VF) using an ongoing electrical current.
Yet our study was unique, because until then, nobody knew why this damage happened. Now we did: it was inadequate blood flow to the inner muscle.
The expected 40% greater blood flow to the inner shell did not occur when a constant current was used — and this undernourishment caused severe damage. The likely cause was further compression of the blood vessels inside its quivering muscle. The continuous current made the ventricle squeeze more vigorously.
The light of understanding was now beaming upon us, and how delighted we were! These studies had finally uncovered and documented why the heart sustained damage when ventricular fibrillation was used during cardiac operations!
But there was one more study that we needed to do… and it yielded remarkable findings on its own.
Unhealthy Hearts Hurt More than Helped
I understood our studies had impact, but I also recognized that our findings were incomplete — because sometimes using only a momentary electrical stimulus in operations did not always work either. Some patients sustained heart damage, and we did not understand how that could be.
Solving the Mysteries of Heart Disease Page 6