Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  Looking Toward Tomorrow

  While everyone celebrates the fact that opening the closed artery reduces the immediate loss of life from 20% to 5% after a heart attack… these treatments often only postpone the mortality. The patient may not die right away or in the first year, but a 1993 report documented that about 20% of them with substantial muscle damage will develop congestive heart failure, and succumb earlier than otherwise expected.23 This conclusion is now amplified, as recent reports from England (in 896 patients),24 the Mayo Clinic (1992 patients),25 and Italy (284 patients)26 demonstrate that delayed heart failure develops in about 30% of patients sustaining an acute heart attack. Each study clarifies that successful angioplasty does not prevent this disastrous complication.

  This is because today’s treatments don’t save the entire heart muscle. They simply limit the extent of injury and cell death to the inner and mid-regions of the heart. Although the area of muscle damaged by the heart attack is not contracting, its surface appearance appears normal. In fact, cardiac surgeons believe that the region is healthy because its surface looks normal in the operating room. Yet this unmarked exterior camouflages a severe underlying internal injury. This deeper injury is the basic cause behind heart failure, the world’s leading cause of death. (This problem will be further described and solved in subsequent chapters).

  Conversely, because of traditional acceptance that the heart attack damaged muscle cannot be mended, all efforts are directed toward preserving and improving the remote muscle performance, since that is now the patient’s lifeline. The key to this is that the remote muscle must be well-nourished by blood. Yet it is not uncommon for the arteries feeding it to be narrowed as well. Thus, the remote muscle is vulnerable to sustaining further damage because its need for increased blood flow may not be met. The aftermath of such injury is the triggering of glaring consequences: the heart will develop a drastic complication called cardiogenic shock, leading to its acute failure. A tragedy that is not pleasant to behold.

  Stealing Away Life

  As a surgeon who is asked to see patients in the coronary care unit, I vividly recall a prominent and influential businessman in his early 60s who’d had a severe heart attack and was suffering from cardiogenic shock.

  When I approached his bed, his breathing was rapid and shallow. His skin had a blue hue and was cool and clammy — symptoms of impaired blood flow to the extremities. Why such symptoms? Because the body is spectacularly struggling to stay alive. Adrenaline is released to raise blood pressure to try to ensure flow to crucial organs, and in doing so, it constricts the small arteries leading to the skin, explaining its blue color and cool and damp appearance.

  My patient had intended to hold a standard business “power meeting” with me in which he would be in control at all times. Yet cardiogenic shock restricted blood flow to all body organs… including the brain. This resulting poor body nourishment eroded his normally strong personality, thinking, and health. His forceful demands never surfaced and he became quiet, bewildered by how his body refused to cooperate. He had morphed from a leader into a suffering patient, leaving his wife to explain the dreadful nature of his illness to the cardiology team. He sat uncomfortably upright due to his congested lungs, while the team administered a range of cardiac support drugs to try to improve performance of the remote muscle… but all to no avail.

  Treatment options are very limited for people in cardiogenic shock. That’s why the intent is to keep anyone from reaching such a severely debilitated state. Otherwise, the only options available to cardiologists are administering drugs to make the remote muscle beat more efficiently, and possibly use pacemakers to ensure a normal heartbeat is retained.

  But these approaches are often inadequate, because the remote muscle’s own ability to function is again often limited due to obstructions in the coronary arteries that nourish it. What typically happens is there is 100% closure of the artery in the heart attack region, with 75% narrowing of arteries supplying the remote muscle. This limitation of flow will undermine the remote muscle’s capacity to compensate for the non-functional damaged heart region.

  While cardiologists won’t typically perform angioplasty on remote muscle, surgeons are asked to perform coronary grafts on it to try to fortify its compensating function. But undertaking this task introduces significant new problems and risks.

  The life of such a heart attack patient is totally dependent on the function of the remote muscle, but it is in a very vulnerable state. If there is inadequate cardiac protection while surgically completing coronary grafts, remote muscle damage will worsen and recovery may not be possible. As a result, cardiogenic shock will continue, even though the remote muscle now receives unobstructed blood flow from the newly placed graft.

  The outcome was that the mortality for coronary graft surgery in these cardiogenic shock patients was as high as 50% in many centers — principally because insufficient cardiac protection resulted in damage to the heart’s only functioning region — its remote muscle. Because of this, surgeons did not want to operate while the heart was still in its weakened state, and recommended delaying coronary grafting until four to six weeks later. Unfortunately, that postponement would be too late to help the fragile remote muscles causing cardiogenic shock, like in our businessman, where mortality is over 75% without surgical treatment (and still 50% with an operation).

  Saving the Remote Muscle — Safely

  I agreed that while coronary grafting could solve the issues with weakened and undernourished remote muscles, it was simply too risky to perform using conventional heart protection methods. However, I believed we could solve this.

  This became our first goal toward improving patient survivability from heart attacks: exploring whether the protective methods that we developed for open-heart procedures (as reported in the prior two chapters) could offset these risks.

  We began by mimicking the same adverse conditions in the hearts of animal test subjects as found in heart attack victims, and then conducted coronary grafting on the remote muscles. So what happened?

  Our cardioplegia protocols found immediate success.19

  We then moved from bench to bedside, using our novel techniques in 80 consecutive patients. Remote muscle was successfully protected in these heart attack victims! Mortality was only 10% — plunging down from the standard 50 to 70% — if we operated within 18 hours after cardiogenic shock developed.27 What’s more, we would later find that five years afterward — these patients still had a 70% survival rate.

  So we not only avoided early mortality, we were also able to significantly reduce later mortality. We established that even though the remote muscle was a stress-vulnerable area, if you protect it well, it does beautifully. In fact, while others were afraid to operate on people already in cardiogenic shock, we firmly believed in our strategies. They were used in the businessman I described earlier. He recovered promptly and became a long-time survivor, recapturing his gusto for life and leadership as well!

  Next Step: Saving More than Remote Muscle

  While our protective methods were successful in saving high-risk patients, our ability to treat all heart attacks was still markedly limited — since the remote muscle was all that we could save.

  So the intense frustration continued, as many heart attack patients experienced long-term decline as they later developed heart failure and lethal arrhythmias.

  As I have described, the patient’s long-term future must only rely upon the performance of the living remote muscle, since the dead muscle from the heart attack did not resume contracting. Later follow up is essential, since successful angioplasty does not prevent about 30% of patients from going on to develop congestive heart failure. Drug treatments will lengthen the patient’s survival, but they do not substantially reverse the heart dilation (stretching) that causes heart failure.

  As a result, a troubling scenario develops. The unsuspecting former heart attack patient could be out golfing, enjoying a beach vacation with his wife,
or watching his granddaughter’s school play… and all the while his remote muscle is stretching, setting the stage for heart failure, much as it did for my dad.

  But with no known way to restore function to the non-contracting muscle region, the cardiologist’s typical response to a heart attack continues: efforts remain focused upon restoring blood flow as fast as possible. It does not solve the deeper issue, as the dead muscle portion still has no function. Yet that reality is disregarded and urgent reperfusion (in this case, opening vessels to return flow) remains the Accepted Wisdom of cardiology strategies.

  That’s when it dawned on me: our prior work on reperfusion injury during cardiac surgery could also be applicable after a heart attack.

  Our mission to immediately save lives must not be our only goal. We must aim toward having patients walk out of the hospital and welcome a lengthy future. That can only occur if we can make the heart attack region recover its ability to function.

  Yet no one was doing this, because the heart attack region was considered dead.

  At least… that’s what everyone believed.

  Searching for a New Reality

  This is the challenge that launched our research in 1981: to see if near-normal function could be returned to the damaged heart attack muscle.

  I believed this damage reflected an ischemic reperfusion injury. That is, the closed artery causes ischemia (no blood to the heart), and returning normal blood reflow to the heart attack region (as done by treating it with angioplasty) causes a reperfusion injury. From everything we had learned previously, as described in prior chapters, I thought we should be able to fix this.

  I knew this approach would directly confront the traditional adamant belief that the “perceived” death of the injured heart region cannot be remedied.

  But such beliefs must be confronted and tested.

  Welcome to our new scientific quest.

  CHAPTER 9

  Restoring Life to

  a “Dead” Heart

  “Miracles” can happen.

  As described in the last chapter, the conventional medical view was that since an absence of blood supply caused the heart attack, immediately opening the artery to give new blood supply (reperfusion) should be the right treatment. Yes, it relieves the dire symptoms of the heart attack (improved blood pressure, cardiac output, filling pressure, heart rate), and favorably brings the dilated (stretched) basketball shape of the heart back toward its elliptical form like a football.

  But while a sense of optimism is buoyed as the seemingly unscathed patient leaves the hospital a few days later… a very different future can unfold that reveals the more complete story (congestive heart failure).

  The reason?

  The primary function of the heart muscle is to contract to nourish the body. Yet returning normal blood reperfusion after a heart attack fails to restore this vital action — as part of the heart remains dead.

  Sitting at my desk, determined to find a way to remedy these acute heart attacks… what initially came to mind was how we used blood cardioplegia to offset the reperfusion injury that follows the temporary absence of blood flow during cardiac surgery. I suddenly suspected that the same type of injury may happen when normal blood flow is returned to the ischemic (blood deprived) region after a heart attack.

  What I knew was this: cardiac contraction cannot recover when even only 50% of the muscle is terminally injured22 — the damage doesn’t have to be 100%. Yet such an extent of muscle loss (50% or more) is common when regular blood is used for reflow after a heart attack.

  As I considered this, a new light began to shine. The delivery of controlled reperfusion itself is straightforward because only two primary factors are involved. The first is the “composition” of the blood being returned, where substances would be added to normal blood to protect the heart, much like the gasoline additives to make your car’s engine run more smoothly. The second is controlling the “conditions” of the reperfusion by adjusting pressure, ventricular volume or stretch, temperature, and flow rate.

  But treating an acute heart attack was a new challenge — since many believed the muscle had sustained irreversible damage. Overcoming this conventional belief could be done in only one way: by proving that using controlled reperfusion (instead of normal blood) could restore contraction to the heart attack region that was presumed to be dead.

  At the same time, I also knew there would be staunch opposition from cardiology teams to adopt the newer method of controlled reperfusion being used in cardiac surgery, since it takes longer to administer, and they believe their principal mission is to quickly deliver regular blood reperfusion. Their rallying cry, “The longer the heart goes without a blood supply, the greater the muscle death will be,” seemed set in stone. But I believed the best yardstick for patient recovery must be finding an approach that restores the heart attack muscle’s ability to contract again, rather than focusing upon a battle against the clock. Angioplasty — with normal blood reperfusion — simply cannot achieve this goal of ensuring the heart attack muscle’s recovery.

  In order to tackle this problem, I needed to more deeply explore the concept of presumed “irreversible damage” after an acute heart attack. I knew that despite the advantages of controlled reperfusion, it can never make a dead muscle resume beating.

  But what if it did make it beat?

  Diving Deeper

  There were two accepted methods for determining irreversible damage (to document death of heart tissue) and both were conducted during postmortem (autopsy) examination. Researchers would place the injured heart segment in a tissue-staining fluid to perform a TTC (triphenyl tetrazolium chloride) stain. If the muscle sample stained a yellow color, it was deemed to have become necrotic (dead). The other method was to get a microscopic analysis of the mitochondria (tiny cellular structures) — which as you may recall from high school biology, control energy production in the heart. If they were disrupted, that meant the muscle had died, and it would foreshadow the patient’s demise.

  These methods had been used to verify irreversible damage in experiments by others, in which the blood supply to a region of a heart was stopped for 40 minutes, and then flow was returned. The functional findings showed the injured muscle did not squeeze, and became thickened and rigid (“contracture”). This complication was most severe in the heart’s inner shell — and was triggered by the abundance of calcium that accumulated in damaged muscle cells, together with a disruption of the fragile mitochondria that use oxygen to produce energy.

  These severe changes in performance, and associated lab results, were consistent. Yet that did not deter us from asking: Was this injured region truly dead?

  An Accidental Breakthrough

  As investigators, we wanted to first match what others reported. So we reproduced the 40 minutes of no blood supply in a test animal’s heart, and noted the heart just sat there after the reflow was started. Not squeezing, like it was dead.

  But just as we had concluded the procedure, an unexpected and new adventure unfolded.

  My hand accidently touched the heart when I reached for something.

  That’s when it happened.

  I stood straight up, taken aback. “What the…? Did you see that?”

  “See what?” asked one of the team.

  “Touch the heart.”

  “Excuse me? Why do you want us to…”

  “Just touch the heart,” I insisted.

  He did. It happened again. “Wow — astounding! It moved!”

  I smiled. “I know. This dead muscle — isn’t dead. It may not be beating, but it sure ain’t dead.”

  No one could believe it… yet there was no denying what we saw. As you might imagine, the observation raised an exciting new question:

  “So if it’s not dead — then what is it?”

  We knew it was still injured. In a sense, it was stunned, but it could be temporarily aroused. I subsequently would learn that others had described this “stimulated” beat, but
I was unaware of this when it happened in our study. What we were witnessing was not a normal heartbeat. It would only move when poked and only once each time. It’s what would be called an ectopic heartbeat, which means this portion of the heart develops its own periodic beat that doesn’t coordinate with the rest of the heart beating normally. It’s not a useful beat as the heart does not pump, but there is no escaping that a contracting motion came from living muscle in a region thought to be dead.

  This observation was vital — because dead regions never move. A cardiology friend of mine, Jan Tillisch, put this into colorful perspective by observing, “Steak does not beat.”

  But how could such a contradiction to conventional thinking occur?

  Collaborative Endeavor

  A unique benefit of working at a university is the ability to meet individuals with extensive experience in common areas of interest. We encounter each other at staff meetings, conferences, or through friends. We speak of our work with passion, looking for ways to support shared aims, always hoping to find a companion to tread with us on a newly forged trail.

  It was just such an encounter that introduced me to Fritiof Sjöstrand, a Swedish physician and histologist (one who studies microscopic structure of tissue) at UCLA who was a pioneer in his field. Aside from a deep mutual interest in the heart, Fritiof was a marathon runner (at 75 years old) and I was a marathon swimmer. Focus, persistence, and overcoming obstacles were scientific and athletic qualities we shared — traits I liked to believe my Grandpa Zelig would be proud of, if he were alive to see them.

  Fritiof agreed to join forces with my team during our experimental studies of acute heart attacks. We were both eager to bring new information to light on the effects of prolonged ischemia (lack of blood flow to the heart) and its treatment. Our aim was to blend his new method of ultrastructure tissue analysis with our innovative functional treatment of hearts undergoing a heart attack.