Heart

by Sandeep Jauhar

  The heart’s conduction system: SAN, sinoatrial node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle. Dashed lines represent atrial activation; solid lines represent pathways for ventricular activation. (Courtesy of R. E. Klabunde, www.cvphysiology.com, 2017)

  By the turn of the century, this paradigm had largely been laid out. Scientists understood that the heartbeat is powered by electricity generated in the right atrium and conducted southward, stimulating billions of electrically coupled cells along the way. What took longer to appreciate is that when the heart stops beating, that is usually because of electricity, too.

  George Mines, circa 1914 (Courtesy of Physiological Laboratory, Cambridge University, England. Reprinted with permission)

  The key figure to explain this connection was the Englishman George Mines, a product of the famed Cambridge School of Physiology. As a young man, Mines was a piano prodigy and briefly considered a career as a musician. This predilection for rhythms stayed with him. He received his PhD from Cambridge in 1912, when he was twenty-six. An avid photographer, Mines introduced the moving-image camera to cardiac physiology, recording the contractions of a pithed frog’s heart by photographing it at fifteen frames per second on bromide paper, using a method pioneered by a close acquaintance, the cinematographer Lucien Bull. After he graduated from Cambridge, Mines did postdoctoral sabbaticals in England, Italy, and France before accepting a professorship in physiology at McGill University in Montreal. Mines’s two most important discoveries—perhaps the most fundamental in the history of cardiac electrophysiology—were made during this period, in experiments he conducted on tortoises, fish, and frogs.

  The first discovery was that small electrical channels can exist outside the normal conduction pathway in the heart. Normally, these extraneous circuits are excited uniformly and do not alter the heartbeat. But if one side of such a circuit—call it side A—has a longer refractory period than side B, because of illness or electrolyte disturbance or injury from a heart attack, for example, it may be in a refractory state when a premature impulse arrives and will therefore not conduct. The impulse will travel only down side B, which has recovered excitability because of its shorter refractory period. Mines’s great insight was that if side A recovers excitability before the impulse reaches the bottom of the circuit, the impulse may conduct back up side A and then again down side B (which quickly recovers excitability because of its shorter refractory period), repeating this pattern over and over. Theoretically, the impulse could circulate indefinitely, without any further external stimulation. With every rotation, a portion of the circulating wave can leak out of the circuit and activate surrounding heart tissue, like a lighthouse beacon sending its signal to faraway ships. In this way, the circulating wave could usurp the activity of the sinoatrial node and become the dominant pacesetter in the heart.

  Mines called this phenomenon “reentry,” and he was able to visualize the circulating current in experiments on rings of jellyfish. He published a classic figure still in use (akin to the one shown below) that illustrates “circus movement” in these myocardial circuits and how such movement can initiate rapid arrhythmias. He also showed that cutting the circuit will instantly terminate the circulating wave, an observation that is the basis for surgical treatment of many arrhythmias today.

  Cardiac reentry (Created by Liam Eisenberg, Koyo Designs)

  The modern depiction of reentry preserves Mines’s essential insight. In this scheme, a circulating (or spiral) wave is set up in the presence of nonconductive tissue, such as a scar formed after a heart attack. If the scar is small compared with the wavelength of the impulse, the waves hardly notice it—as when water waves pass over a tiny pebble unperturbed.

  But if the obstacle is large, the wave can break, the edges lagging behind as the rest of the wave moves ahead, thus causing the segments to begin to curl (as when flowing water encounters a large rock and forms an eddy current downstream). Far enough out, the wave edges become the center of circular (or spiral) waves.

  The circular pattern reflects the need for refractory heart tissue to return to an excitable state in order for the wave to propagate and not die out. The simplest pattern to do this is a spiral, that iconic image of psychedelia, that anchors at one point, circulates, and slowly moves outward. As Mines discovered in his experiments on jellyfish, these spiral waves are selfsustaining: they can constantly reenter tissue that has recovered its excitability and persist indefinitely.

  Wave hitting a small obstruction

  Wave hitting a large obstruction

  Spiral wave in a computer model of cardiac tissue (Courtesy of Alan Garfinkel)

  Spiral waves are ubiquitous in nature. They are created when smoke flows through cold air (see the picture on page 146) or when water flows across pebbles. They occur in superconductors and multicellular aggregates of amoebas, and in many chemical reactions, too. Even the visible mass in the universe is organized into spiral galaxies. With so many natural manifestations, it is no surprise that this pattern is seen in the heart as well.

  Though Mines observed reentry only in lower animals, mostly fish, the phenomenon was soon confirmed in human hearts in 1924. It is now widely accepted that spiral wave reentry underlies most abnormally fast heart rhythms, including ventricular fibrillation, the most common cause of cardiovascular death in the Western world.

  In ventricular fibrillation, the heartbeat is so rapid and irregular that effective pumping of blood ceases to the brain, lungs, and other vital organs, resulting in a precipitous drop in blood pressure and the almost immediate onset of cell death. Though the heart is still quivering, blood flow has essentially stopped.* “Sudden cardiac failure does not usually take the form of a simple ventricular standstill,” the Scottish physiologist John Alexander MacWilliam wrote in 1889. “It assumes, on the contrary, the form of violent, though irregular and uncoordinated, manifestations of ventricular energy.” Every hour in the United States, forty people suffer an out-of-hospital cardiac arrest, mostly because of ventricular fibrillation. Fewer than one in ten survive. Ninety percent don’t even make it to the hospital alive. Ethnic minorities and lower socioeconomic communities fare the worst, perhaps because of a lack of access to external defibrillators and a lack of education in bystander CPR. Survival after in-hospital cardiac arrest isn’t much higher, about 25 percent. During the past several decades, mortality has decreased because of the proliferation of cardiac care units, community-based emergency rescue programs, and developments in cardiac electrophysiology. Yet ventricular fibrillation remains a death sentence for millions worldwide. An American dies of cardiovascular disease (including stroke and heart failure) every thirty-three seconds, accounting for about one in four deaths nationwide, and the terminal event in most of those deaths is ventricular fibrillation. Purveyor of life, the heart is also its Grim Reaper.

  Ventricular fibrillation most often occurs in diseased hearts, where damaged cells and disrupted electrical signaling create the conditions for reentry. However—and this should come as a shock—fibrillation can occur in normal hearts, too. In what was perhaps his most important discovery, Mines experimentally determined that there is a narrow period in the cardiac cycle—a “vulnerable period,” he called it, about ten milliseconds in duration—during which a stimulus—an electrical shock or even a punch to the chest, in which mechanical energy is converted to electrical energy—can cause a perfectly normal heart to fibrillate and stop. To show this, Mines developed an apparatus to deliver single electrical shocks via taps of a Morse key to platinum electrodes placed on the ventricles of a rabbit’s heart. In a number of instances, he found that “a single tap of the Morse key if properly timed would start fibrillation.” The timing was crucial. “The stimulus employed would never cause fibrillation unless it was set in at a certain critical instant,” Mines wrote. A stimulus delivered before the vulnerable period would do nothing; after the vulnerable period, the stimulus would merely initiate an
extra heartbeat. But a stimulus applied within the vulnerable period could excite tissue just recovering from the last beat and precipitate fibrillation. In his 1913 report “On Dynamic Equilibrium in the Heart,” Mines wrote that his findings “suggest an explanation of the important and interesting condition of delirium cordis,” or madness of the heart.

  The vulnerable period is crucial to understanding why normal hearts can self-electrocute. For example, when a healthy young athlete drops dead after getting a blow to the chest from a baseball or hockey puck, it is because the heart was hit during its vulnerable period. Scientists have confirmed the presence of the vulnerable period in mammals by slamming a baseball mounted at the end of an aluminum shaft into the chests of eight-to twelve-week-old anesthetized piglets at various times in the cardiac cycle. They found that when the impact occurs within a narrow window 10 milliseconds long and approximately 350 milliseconds after the previous heartbeat, it can induce cardiac arrest.

  The explanation behind ventricular fibrillation in normal hearts is often also reentry. In a diseased heart with scar tissue, the mechanism is obvious: as we have seen, a wave breaks by interacting with inert scar tissue, forming spirals out of its edges. But reentry can occur even when there is no scar. In this case, a wave breaks by interacting with another wave, spinning around the refractory tissue formed in the other wave’s wake as if a scar were present. This is known as “functional” reentry (as opposed to the “anatomic” reentry) and is just as deadly. The impulse that induces the spiral wave must occur at exactly the right time and place to collide with the wake of a previous wave. This is precisely the vulnerable period that Mines discovered in his rabbit experiments.

  The first experimental observation of cardiac spiral waves was made by José Jalife and his colleagues at Syracuse University in 1992 and published in the journal Nature. Using a special camera to detect fluorescence from canine heart tissue injected with specific chemicals, they produced an image with the shape of a counter-rotating spiral with a size of about two centimeters. Jalife’s group found that these spirals often anchor at scars or other inhomogeneities and can theoretically circulate indefinitely, each turn bringing the signal back to full strength, as Mines first showed.

  Jalife also discovered that a spiral wave does not have to remain at a fixed position. When the spiral moves, it can start to meander, like a top slowing down on a table, its tip tracing a curlicue pattern. Eventually, the spiral wave can pick up so many oscillations that it breaks up, creating multiple independent spirals that stimulate the heart in a disordered fashion, as when waves collide at the shore, leaving thick, turbulent foam. This is ventricular fibrillation, an arrhythmia so fervent, so committed, so devoted to its mission that you literally have to shock it out of the heart to make it stop. The Scottish physiologist MacWilliam wrote of ventricular fibrillation in 1897, “The ventricular muscle is thrown into a state of irregular contraction, whilst there is a great fall in the arterial blood pressure. The ventricles become dilated with blood as the rapid quivering movement of their walls is insufficient to expel their contents.” This is essentially electrical chaos, and the heart (and its owner) quickly die.*

  In a 2000 study in the Proceedings of the National Academy of Sciences, Alan Garfinkel and his colleagues at UCLA imaged slices of pig hearts using a special microscope to show that when the tissue fibrillated, spiral waves were breaking up into multiple new waves that activated the heart in a chaotic pattern. It is not known precisely why spiral waves break up, resulting in fibrillation, but it is believed to depend on how quickly heart cells recover their ability to be re-excited, a property known as restitution. Restitution depends on many factors, but it can be amplified by lack of coronary blood flow—the mechanism that killed both my grandfathers—as well as by surges of adrenaline during psychological stress. Whatever the reason, when heart cells become more excitable, a spiral wave can become exquisitely sensitive to small perturbations in the electrical environment, picking up oscillations and setting up the conditions for breakup. “Steepening” of cardiac restitution may even be the mechanism behind “voodoo death,” the mysterious, sudden demise documented by anthropologists that often occurs during periods of intense emotional stress, such as after a witch doctor’s curse. Beta-blocking drugs that antagonize adrenaline have proved effective in preventing such fatal arrhythmias, which is perhaps why Mitch Shapiro, the Bellevue electrophysiologist, often said that beta-blockers should be put into New York City’s water supply.

  •

  Mines’s research on reentry and the vulnerable period inspired a new era in cardiac electrophysiology. Unfortunately, he did not live long enough to see the impact of his work. On the chilly Saturday evening of November 7, 1914, a janitor entered Mines’s laboratory at McGill to find him lying unconscious under a lab bench with monitoring equipment attached to his body. He was rushed to the hospital but died shortly before midnight without recovering consciousness. Though an autopsy was inconclusive, medical historians believe his death was the result of experimentation on the vulnerable period in a human: himself. This speculation was fueled by a lecture that Mines delivered to McGill faculty one month before his death, when he was twenty-eight. In the talk, Mines spoke in praise of self-experimentation, referring to the work of contemporaries who severed their own nerves to understand the nature of skin sensations or swallowed a plastic tube to study the physiology of digestion. Evidently, Mines decided to put his theory of the vulnerable period to the test on himself. Mines did not know about Werner Forssmann. His tragic self-experiment predated the great German’s self-catheterization by fifteen years.

  *Ventricular fibrillation was probably first described by Andreas Vesalius, who observed that animals deprived of oxygen develop a wavy, wriggling motion of the heart.

  *The idea that an excitable system can degenerate into chaos was first suggested by David Ruelle and Floris Takens in a 1971 paper titled “On the Nature of Turbulence.” They proved mathematically that a system containing three or more coupled oscillations is inherently unstable. Their predictions were experimentally confirmed in studies of fluid dynamics and later electronic materials. Their work showed that ventricular fibrillation is a form of spatial and temporal chaos.

  10

  Generator

  When a condition is recognized as offering only a fatal or hopeless outlook, desperate measures seem less desperate and with application and courage not infrequently can be made safe.

  —Charles P. Bailey, cardiac surgeon, Hahnemann Medical College, Philadelphia

  “I told him that if he doesn’t do something, he’s going to be dead by the end of the year,” Shawn, my magnet-wearing patient Jack’s visiting nurse, told me on the phone one afternoon. “His heart is going to conk out, and he doesn’t have time to play with these so-called nutraceuticals.” Shawn paused, obviously frustrated. “You know what he said to me?” Shawn spit out the words in disgust. “‘Will it be painless?’”

  I’d been calling Jack, my clinic patient, about once a week to check on him, but despite worsening heart failure he’d been resistant to my recommendations, convinced that his herbals and magnets would eventually work. Because of a lack of family and social support, Jack wasn’t eligible for a heart transplant. There was no one available to assist him with chores or ensure he’d make it to his appointments or take his medicine. His only options were a $40,000 surgically implanted defibrillator—or hospice. I didn’t hear anything for a few days. Then Shawn called to tell me that Jack was feeling sick again. He was sleeping sitting up in a chair because of the fluid accumulating in his lungs and was waking up every couple of hours gasping for air. Shawn had finally persuaded him to get the device.

  I admitted Jack to the CCU at Bellevue and scheduled a cardiac catheterization prior to the implant. True to form, he quickly became annoyed with the hospital staff. One morning I was urgently paged to the unit because Jack was fighting with the nurses to go home. When I arrived, he was in a small, curtained space, lyi
ng on crumpled sheets in a fetal position. Thin plastic tubing delivering supplemental oxygen was pressed tightly against his sunken cheeks. I immediately turned the green knob controlling the flow of oxygen. A tiny ball bearing shot up in a plastic meter, suspended by the increased flow of air.

  “I’m having pain in the middle of my chest,” Jack said, without looking at me. A stained white knit cap had replaced his bowler. He looked even more emaciated than when I’d seen him in the clinic. I felt pity, but a bit angry, too. “This is why you need an angiogram, Jack,” I said.

  “You should have done it this morning,” he growled, his eyes flashing anger even as they tried to close. “That’s another day lost.”

  I told him the test was scheduled for the following day. If his coronaries were clean, we would implant the defibrillator immediately afterward.

  “You’re saying one thing; other people are saying something else.”

  “Well, I’m running the show here,” I said quickly. As a senior cardiology fellow, it was nice to be able to say that I was finally in charge, at least of the care of my clinic patients.

  “The consent form mentioned emergency bypass surgery,” Jack continued monotone. “I don’t want that.”

  That was just consent-form boilerplate, I explained. Every possible risk had to be included on the form in the unlikely event of a serious complication.

  “My life was fine until you came in and started pushing your weight around,” Jack said, trying to sit up.

  “I think you’re misinterpreting.”