by Rob Dunn
It appears that in children with ventricular-septal defects, the expression of this gene goes wrong. In these children, the gene is expressed in the old way, the way it once was in our lizardlike ancestors. This leads to a lack of a wall between the ventricles, or a hole between the ventricles. Although it has not been well worked out yet, many other congenital disorders of the right ventricle, perhaps even including the tetralogy of Fallot, also relate to the expression of this gene. We still do not know what proportion of congenital heart diseases are genetic, but it is clearly higher than thought during Taussig’s life. It may be very nearly all of them.
Taussig, despite her age, or perhaps because of her age and perspective, was right. Other scientists have only just begun to catch up to the ways in which she was right. Although individual studies confirm that most congenital heart defects are genetic, and although detailed genetic studies of a few congenital diseases demonstrate the ways in which they are layered on our ancient genes, no one has followed up on Taussig’s work to study the evolution of congenital heart diseases.9 We do not yet know whether the ventricular-septal defects in birds are due to similar mechanisms as those in mammals. We do not even know any more than she did about which congenital deformities birds suffer from. Taussig’s catalog of the broken hearts of birds still remains the most comprehensive.
Understanding the evolution of our hearts has allowed us to better understand their deformities and disease. But Taussig did not anticipate how broad the lessons from evolution might be. Considering the evolution of our hearts sheds light on their weakest parts, their coronary arteries.
Today, in most mammals, the coronary arteries are two short arteries that each branch into smaller arteries on which an individual’s life depends. If any of them clog, death of the regions of heart it feeds ensues. Often, this is enough to stop the heart; the afflicted suffers chest pain, shortness of breath, and then loss of oxygen to the brain. But even if it doesn’t stop, the heart is slow to recover, and the affected muscle is replaced by scar tissue.
These two main arteries, left and right, arise in the aorta and supply blood to the heart. They are the first to branch off the aorta, even before the artery leading to the brain. They are at the root of the phrase to have a coronary. But what has long been considered unusual about these arteries is why there are just two to start with, with no backup plan. This, like the congenital deformities, might have an evolutionary explanation as well.
Our human coronary arteries evolved in concert with the evolution of the four-chambered heart. Coronary arteries have evolved again and again in vertebrates to deal with increased levels of activity. Fast, long-swimming fish developed long coronary arteries that run from the gills to the heart (in essence, an extra cycle), for example. But the most conspicuous coronary arteries are found in mammals and birds. Both mammals and birds evolved greatly expanded coronary arteries as the activity and efficiency of their hearts increased. The expanded coronary arteries of birds and mammals were required to deal with the extra activity of the heart in general, but the most acute challenge may have been the left ventricle, which, once it became totally separated from the right, no longer received the slosh of oxygenated blood10 (though once coronary arteries were present on the right, they were useful on both sides).
Coronary arteries existed in the ancestral lungfish and also in amphibians, snakes, lizards, and turtles, but they were modest in size and flow. They derived from two narrow branches off the aorta, but that was enough. In mammals and birds, the size of the ancestral coronary arteries increased, as did the web of their arterioles and capillaries, but their number, just two, stayed the same. It was easier for evolution to expand these arteries than to make more of them.
In mammals and birds, coronary arteries are now necessary for everything. Our active, warm-blooded existence depends on them. With our hard-charging hearts (and lives), if these arteries get clogged, the heart will not have enough oxygen to pump. It dies. If engineers were designing a heart from scratch, they would give it more coronary arteries for backup. They would arrange things differently. But evolution does not design from scratch; it built our hearts out of lungfish hearts, which were built out of earlier fish hearts, which were built out of sponges’ cardiovascular systems. Where mammal species differ at all with regard to coronary arteries, the differences have to do with very small vessels, the collaterals, which run crosswise between coronary arteries. In some species, such as dogs, these vessels are relatively large, whereas in other species, such as pigs, they are nearly absent. In healthy humans, these collaterals carry less than 2 percent of the flow found in the coronary arteries. We depend on the coronary arteries. Our history is our context but also our weakness—we have just two coronary arteries when more would be useful. We are predisposed to die the way we do because our ancestors crawled onto land and evolved warm-bloodedness. Our active success gave us an Achilles artery.
It is this weakness that heart surgeons dealing with clogged coronary arteries confront, a weakness due to our origins, a weakness with its roots in the transition out of the sea. But it gets more complex. The coronary arteries are a weakness only because they clog due to atherosclerosis. In theory, evolution might also shed some light on the heart’s weaknesses by helping us to understand when our hearts began to clog. We know that atherosclerosis is as ancient as Queen Meryet-Amun’s reign in Egypt. But it could conceivably go all the way back to the first mammal (or bird). Amazingly, this is a possibility no one even considered until a few years ago, when Dr. Nissi Varki and, later, her husband, Ajit, began to look at chimpanzee hearts.
16
Sugarcoating Heart Disease
In 2005 Nissi Varki became deeply intrigued by reports at a meeting of primatologists in La Jolla, California, not far from her house. This intrigue would lead her to a discovery that has changed the understanding of heart disease in humans. At the meeting, scientists from five primate centers, including the Yerkes National Primate Research Center at Emory University, summarized their observations on the causes of deaths among captive chimpanzees. It was, or should have been, really boring, nothing more than a tallying of the final moments of dozens of captive animals.
In the wild, predators, snakes, infections, and other chimpanzees kill chimpanzees. In zoos and research facilities, chimpanzees are removed from most of these threats, and so, it was presumed, they lived long enough to suffer terrible chronic diseases. Yet, although the fates of zoo and laboratory chimpanzees were studied in autopsies, they were not studied from any sort of broad perspective. The literature, to the extent that it weighed in at all, seemed to assume that chimpanzees died of exactly the same diseases in captivity that humans die of in modernity: heart disease, strokes, and cancer.1
At the Yerkes laboratory and in other primate centers, predators are kept at bay, diseases are controlled, and the animals eat processed diets (in most cases, Purina monkey chow. Yes, Purina sells monkey chow) supplemented with vegetables and bread. Well-fed chimpanzees move inside their cages, banging around and killing time while exercising much less than they would in the wild. Based on their diet and lifestyles, one might expect captive chimpanzees to have heart attacks, at least occasionally. It did not, then, come as a surprise when talks at the meeting in La Jolla revealed that heart disease was a very common cause of death in the Yerkes chimpanzees—perhaps the most common cause of death, particularly among males, just as in humans. Other studies showed that these same animals also had very high levels of cholesterol. This is not good news if you are a chimp, but it made us, as humans, seem less alone in our plight. When living like us, chimps, our closest relatives, die of heart attacks like us.
Superficially, the hearts of different primates tend to be relatively similar. A gorilla heart looks like the heart of a chimpanzee, and a chimpanzee’s heart is similar enough to a human’s that in 1964, James Hardy at the University of Mississippi Medical Center successfully transplanted the heart of a chimpanzee into the body of a human patient, Boyd Rus
h (and Richard Lower later clandestinely transplanted human hearts into baboons).2 The reality that human and chimpanzee (or baboon) hearts can replace each other, even if only very temporarily, could be interpreted as meaning that our shared ancestors also had hearts like us, including the predisposition to heart disease, given the right circumstances. Heart disease, then, in this retelling, is a potential fate far older than ancient Egypt; it is at least as old as apes, and may extend far back into our mammalian past, to the origin of coronary arteries. An alternative scenario—that chimpanzees and humans independently evolved a propensity for the disease—is less parsimonious (that is, it requires more steps). But sometimes two things that look the same are really different. The meeting in La Jolla energized Nissi Varki to think more about the mysteries of the differences between the diseases of humans and chimpanzees. She decided to temporarily abandon the studies of cancer (in mice) that had occupied most of her career to focus on the pathology of chimpanzees. It was not her first foray into the study of chimpanzees; she had helped with several chimpanzee autopsies in the past. But this was different; this would turn out to be a mystery like none she had considered before.
Often it is said that chimpanzees and humans share 98.5 percent of their genetic code, their DNA sequences, which is true, but a great deal of difference can be found in that 1.5 percent. We know about many of the differences between chimps and humans, differences that evolved rapidly. In the few million years that separate us from the chimps, we lost our fur. We stood upright. Our brains became bulbous, heavy with consciousness. Our feet flattened. Our sweat glands became larger and denser. But the internal features of our bodies—skeletons excepted—are thought to have gone through this historic transition relatively unchanged. They were, the logic was, too fundamental for evolution to tweak; a kidney is a kidney, a liver a liver, a heart a heart—hence the feasibility of cross-species transplants.
But when Nissi started studying chimpanzee hearts, she immediately noticed differences, differences the veterinarians seemed to know about but that had gone largely unmentioned in the human medical research literature. To Nissi, it was clear that at least some of the chimp heart attacks were fundamentally different from human heart attacks. Some of the chimps had suffered interstitial myocardial fibrosis, where interstitial refers to the location of the problem (in the gaps between muscles), myocardial means “heart muscle,” and fibrosis is the formation of excess connective tissue.3 Put it all together and you have the formation of excess connective tissue between heart muscles—the heart becomes bound by its own nonfunctional fibers. While it is not totally clear how myocardial fibrosis starts or kills, one hypothesis is that the disease is triggered by an infection that leads to scarring and fibrosis in the heart and, ultimately, to fatal arrhythmias, in which the heart’s beat is no longer synchronized. The fibrosis of the heart muscles prevents the contractions of the heart from moving smoothly from one side to the next, much in the way that oil on the surface of the sea can dampen a wave. Heart attacks due to fibrosis tend to cause sudden death. One moment a chimpanzee is excitedly running around a cage, swinging her arms in the air; the next, she is dead. That such heart attacks occurred in chimps was clear; less clear was how common they were and how they were different from what occurred in the hearts of humans.
Nissi Varki decided to work with veterinary pathologists to study the deaths of chimpanzees at Yerkes along with those at another facility, the Primate Foundation of Arizona,4 in more detail. She looked at preserved specimens of the hearts of chimpanzees that had died in captivity. She was in luck. Biologists, including those at primate centers, are natural hoarders. They collect everything in the hope that something might someday be useful.5 The refrigerators and drawers of biology buildings tend to be filled with a miscellany of dead nature: frozen bats, half a woodpecker, tissue samples, a pinecone.6
In storage, Varki found samples of the hearts of fifty-two chimpanzees, each one stored in paraffin wax. But before looking at these hearts, Varki repeated what had been done before: she looked at the data the chimp caretakers themselves had recorded as to the causes of the chimpanzees’ deaths. In most cases, autopsies had been done, and most of the chimpanzee deaths from 1961 to 1991 were due to infections. But after 1991, once treatment of infections had improved, the most common cause of death, 36 percent of the total (and twenty-one individual deaths), was heart disease.
This was not surprising; it was roughly what had already been reported, with a few more deaths because of the inclusion of slightly more data. But then she and her colleagues examined tissue samples from those diseased hearts, performing what equates to CSI: Chimpanzee. The paraffin samples were pulled out of their paraffin, rehydrated, and then stained so as to make a variety of features of the hearts more visible. When this was done, none showed evidence of severe atherosclerosis. The hearts were largely free of plaques, even though cholesterol levels in chimpanzees matched or exceeded those regarded as healthy for humans.7 Even baby chimpanzees, Nissi Varki learned, have high cholesterol—high enough that if they were humans, they would be prescribed statins. Yet even at these high levels, cholesterol did not appear to be causing most of the heart blockages in chimpanzees. But there was something else. The chimpanzees with heart disease all showed evidence of myocardial fibrosis. Fibrosis was even seen in some of the chimpanzees that had died of other causes. Here was a major discovery, one that changed our perspective on the problems of our hearts.
The simplest explanation for why myocardial fibrosis was so common in chimps but so rarely noted in humans was that it had simply been ignored in humans. Maybe we had just been so focused on atherosclerosis that other problems had been overlooked. To test for such a possibility, Varki paired each ape heart sample with a human heart sample. None of the human hearts showed evidence of fibrosis. Chimpanzees and humans both suffer heart disease, but it is not the same disease. So who is strange, humans or chimpanzees? Nissi Varki considered other apes—gorillas and orangutans. The data were sparse, yet nearly every case—two orangutans at the National Zoo, a series of sudden deaths in gorillas—seemed to suggest fibrosis rather than atherosclerosis as the cause. The same for monkeys, where data existed.
Cholesterol levels in captive chimpanzees and modern humans (living in the United States). The average chimpanzee has cholesterol levels both in terms of total cholesterol and LDL akin to those found in aging humans in the United States. (Data from Evolutionary Applications ISSN 1752-4571)
What about the closest relatives of primates, rodents? Rodents do not appear to suffer from either form of heart disease, neither myocardial fibrosis nor blockage-induced heart attacks. In fact, even mice with extraordinarily high cholesterol levels, levels that would be regarded as acutely dangerous in humans, do not suffer heart disease (the exception being specialized mice bred to be predisposed to heart disease). It was humans, Nissi Varki concluded, who were strange. As she put it, “Rather than representing a similarity, heart disease is an instance where there are unexplained human-specific differences” from the other apes, differences even from other mammals. We die in an unusual way.
If we are to reconstruct what happened that led our hearts to suffer fates different from those of living apes, we need to return to the evolutionary tree. Among living primates, humans are most closely related to chimpanzees and bonobos, their libidinous cousins, from whom our ancestors diverged about five million years ago. The branch that includes humans, bonobos, and chimps branched from that containing gorillas about eight million years ago (which branched from that with orangutans and gibbons even more remotely, twelve and fifteen million years ago, respectively). If all the other apes suffer from myocardial fibrosis while humans alone suffer from atherosclerosis, there are two possible explanations. One is that each of those ape species (and the monkeys and the mice) independently evolved some feature of the heart or immune system that led to fibrosis. The other is that human hearts have evolved special attributes that, while they reduce (or eliminate) the risk o
f myocardial fibrosis, predispose us to an equally fatal fate. Of these two options, parsimony suggests it is far more likely that the latter is true—that our species is the odd one. If I were to write a book about chimpanzee hearts or gorilla hearts or mammal hearts more generally, I wouldn’t even need to mention atherosclerosis or clogged hearts except to note how strange humans are.
Nissi Varki needed to account for not only the absence of the ape form of heart disease in humans but also the presence of the uniquely human form of heart disease we suffer. She can’t explain the heart disease of chimpanzees yet. No one can, nor has anyone really tried. If you would like a mystery to solve, the heart disease of chimpanzees and other apes awaits you (I would start by looking for pathogens in the chimpanzee hearts if I were you). But we can’t ignore our own fate. It is clear our heart disease is not due to having too much cholesterol. Instead, it appears to be due to the body’s response to that cholesterol. Cholesterol flows freely in chimpanzee blood without forming plaques. The plaques in our blood and hearts are due to the immune system’s response to cholesterol and other substances. The human immune system reacts to cholesterol as though it were foreign and smothers it with immune cells called macrophages. Plaques are cholesterol in LDL buried in the artery walls by the accumulation of macrophages. We need, then, to explain why our bodies attack cholesterol while the bodies of the rest of the primates do not. We need to understand the recent evolution of our immune systems to understand our hearts.
