快猫短视频

IT鈥橲 spread by coughs and sneezes. And by the time you鈥檙e 20, there鈥檚 a fifty-fifty chance that you鈥檙e carrying the infection. But could Chlamydia pneumoniae really trigger coronary heart disease, that narrowing of the arteries which suffocates the heart muscle and kills more adults worldwide than any other disease. The theory is fuelling one of the fiercest controversies ever seen in the multimillion-dollar industry of cardiovascular research.

The bacterium鈥攐ften called TWAR after the original laboratory strain鈥攊s the prime suspect because its fingerprints keep appearing at the scene of the crime. People with coronary heart disease are likely to have high levels of antibodies to TWAR, suggesting that they have been persistently or repeatedly infected with it. TWAR鈥檚 DNA and proteins keep showing up in atheroma, the fatty, diseased tissue that blocks the coronary arteries. And now, in as yet unpublished research, the bacterium itself has turned up alive and kicking, forcing the sceptics to sit up and take notice.

Some chlamydia experts have even come up with a plausible way of explaining how the common airborne bacterium that enters the body via the lungs could travel to the blood vessels of the heart and wreak havoc. While others claim that C. pneumoniae may explain some of the great puzzles in the pattern of the West鈥檚 epidemic of heart disease.

The researchers are divided into three camps. The first camp suspects that the bacterium is fuelling the process of atherosclerosis that damages tissue and narrows the arteries; the second, think it is in the arteries, but merely as an innocent bystander; and the third, doubt whether it is there at all. 鈥淚t鈥檚 TWAR wars,鈥� says Mark Enzler, a researcher at the Mayo Clinic in Rochester, Minnesota. But everyone agrees on one thing: the question must be answered soon. Coronary heart disease is so common that, even if a bacterium is playing only a bit part, thousands of people could die for want of a simple antibiotic. In Britain alone, for example, almost 170 000 people died of coronary heart disease in 1993. If C. pneumoniae triggered even 5 per cent of those deaths as many as 8500 people might still be alive.

The TWAR wars will intensify this September when researchers gather in Vienna for the first major chlamydia meeting in four years. The factions refer to each other as believers, disbelievers and agnostics, and the believers see themselves as Davids pitted against the Goliaths of the establishment.

There鈥檚 a sense of d茅j脿 vu in all this. It is only in the past five years that another bacterium, Helicobacter pylori, has been officially recognised as the prime cause of stomach ulcers. For decades, the establishment view had been that, like heart disease, ulcers were the price of an unhealthy lifestyle. People who had been lectured for years about avoiding stress and eating regular meals suddenly had their ulcers cured with antibiotics, often in as little as a week. Coronary heart disease is a lot more complicated, but the chlamydia believers are not slow to draw parallels.

Thomas Grayston, an epidemiologist at the University of Washington in Seattle, is so suspicious that C. pneumoniae is directly linked to atherosclerosis that he proposes to find out if antibiotics such as tetracycline or erythromycin will improve the survival rate of people with coronary heart disease. If heart attack patients who receive antibiotics as well as 鈥渃lotbusters鈥� survive longer and in greater numbers than those who receive only clotbusters, he says, the unbelievers will be forced to rethink. 鈥淲ith Helicobacter, nobody paid much attention until treatment trials showed [stomach ulcers] could be affected by antibiotics.鈥�

Separate and different

It was Grayston and his colleagues who first identified C. pneumoniae and showed, in 1989, that it is a separate species from its relatives such as C. trachomatis, a sexually transmitted bacterium. Grayston now wonders whether a chlamydia link can help to explain why death rates from heart disease are falling rapidly in most industrialised regions of the world. Since the mid-1960s, death rates have plummeted by 60 per cent in North America, and by up to 40 per cent in Western Europe. They have also fallen steeply in Australia. Japan鈥檚 death rate from the disease, which was always much lower than the West鈥檚, has also dropped. Only in Eastern Europe are the death rates from heart disease rising.

Improvements in lifestyle cannot easily explain the widespread retreat of coronary heart disease. While the proportion of men who smoke in the West has dropped from half to about a third, and average blood pressure and blood cholesterol levels have fallen, obesity and diabetes鈥攂oth implicated in heart disease鈥攈ave become more common. Grayson says that all the improvements together account for 鈥渁t most half鈥� of the decline in death rates. 鈥淭he reasons for the rest of the decrease are not known.鈥�

He points out that broad-spectrum antibiotics such as tetracycline which kill chlamydia, were introduced at about the time death rates started to fall in the US. If TWAR is playing a role in heart disease, then the widespread use of such antibiotics might be contributing to the decline in the death rate, he says.

But that鈥檚 just naive, say other, more mainstream epidemiologists. The decline coincided not just with antibiotic use but also with 鈥淭V antennas, increased terrorist activity and the women鈥檚 movement,鈥� scoffs William Kannel, an epidemiologist at Boston University and former director of the Framingham Study, the massive investigation that first identified the now familiar risk factors for coronary heart disease such as high blood pressure and cholesterol.

As for the idea that only half of the reduction in death rates from heart disease can be explained, the disbelievers argue that this view is simplistic. They say it doesn鈥檛 take account of the fact that studies usually underestimate the impact of the known risk factors and fail to measure the ways in which these risk factors interact.

What is more, there is another explanation for the drop in deaths from heart disease that some experts prefer. This says that coronary heart disease is caused by malnutrition in the fetus and in early infancy, and the fall in death rates since the 1960s reflects improvements in mothers鈥� nutrition earlier this century (see 鈥淥ff to a bad start鈥�).

But not everyone thinks Grayston naive. Mike Rayner at the University of Oxford, a 鈥渂eliever鈥� who studies changes in the incidence of heart disease, argues that as all attempts to explain trends in cardiovascular disease rely on large doses of speculation 鈥渁ny explanation of the trends is almost as good as any other鈥�. And with that caveat in mind, he points out that the rise of heart disease in the early 20th century and its rapid decline now follows the 鈥渃lassic鈥� pattern of an epidemic, even if over an unusually long period of time. 鈥淪o it is quite possible that infectious disease is playing a role,鈥� he says.

Searching for clues

The controversial trial that first implicated C. pneumoniae in heart attacks began at the end of the 1980s when Finnish researchers led by Pekka Saikku, now at the National Public Health Institute in Oulu, found that people with coronary heart disease are more likely to have high levels of antibodies to the bacterium than healthy people. During the 1990s, the evidence steadily mounted. Using the polymerase chain reaction, Grayston and his colleagues tracked down C. pneumoniae鈥榮 DNA in samples of atheroma taken from people with coronary heart disease. They also picked out the bug鈥檚 proteins in the atheroma, using fluorescent-labelled monoclonal antibodies that bind to them. All told, about 60 per cent of the diseased arteries had some trace of the microorganism, compared to none in the 31 samples of healthy coronary artery. Soon, other laboratories鈥攊n Finland, Italy, Britain, Japan and the US鈥攚ere finding traces of C. pneumoniae in diseased arteries too. And just last week a team led by Joseph Muhlestein at the University of Utah School of Medicine reported in the Journal of the American College of Cardiology that they had found C. pneumoniae protein in 79 per cent of the atheromas from 90 patients.

Getting warmer

It was last year, however, that the chlamydia trail really heated up. James Summersgill and his colleagues at the University of Louisville, Kentucky, told their colleagues at a meeting on infectious diseases in San Francisco that they had managed to grow C. pneumoniae from a diseased coronary artery in a man about to have a heart transplant. For the first time there was solid evidence in diseased arteries of the bacterium itself鈥攏ot just its molecular fingerprints.

Researchers in two other laboratories at the State University of New York, in Brooklyn, and the Providence Medical Center, in Southfield, Michigan, were able to confirm the key finding. While no one is claiming that the results prove chlamydia鈥檚 guilt beyond a shadow of a doubt, 鈥渢his is very convincing evidence that chlamydia is there鈥�, says Summersgill.

鈥淚 was a disbeliever until I saw this,鈥� says Charlotte Gaydos, who heads a chlamydia lab at the Johns Hopkins University in Baltimore. 鈥淚 don鈥檛 think yet we have irrefutable evidence, but I think the evidence is growing.鈥� Summersgill admits, though, that more studies are needed, not least because none of the labs managed to grow live bacteria from samples of coronary artery from eleven other transplant patients, although in half the samples they turned up DNA and protein evidence of the bacteria.

Meanwhile the disbelievers are standing their ground. Ironically, one of the most vocal of their number, Margaret Hammerschlag, is the head of the lab at the State University of New York which confirmed Summersgill鈥檚 finding. Hammerschlag now dismisses that result as little more than a fluke because her own team鈥檚 new studies contradict the findings. In the April issue of the Journal of Infectious Diseases, the Hammerschlag team reported that they had failed to culture C. pneumoniae from 58 samples of atheroma from New York patients, and that only one sample showed traces of the bacteria by any of the other methods. 鈥淗ow do you reconcile our big fat zeros with similar studies that find up to half of the samples positive?鈥� she demands. (Not that Hammerschlag necessarily thinks C. pneumoniae is totally innocent. She is also investigating a link between the bacterium and asthma.)

Like Hammerschlag, Enzler has searched in vain for TWAR in a set of atheroma samples. Unlike her, however, he thinks the bacterium is probably there if not as often as Grayston鈥檚 lab claims鈥攊t is, after all, notoriously difficult to culture. Others suggest the Grayston labs鈥� bacterial sightings may be due to contamination鈥攖he bane of all labs using PCR. But Grayston is unshakeable: 鈥淚 am confident that our positive results are not false,鈥� he says.

Whether C. pneumoniae turns out to be in most diseased arteries or just a few, a key question must still be answered: is Chlamydia, the commonplace microbe that may be spread in a cough or a sneeze, merely guilty of being in the wrong place at the wrong time or does it really injure the heart鈥檚 blood vessels? Now, interested parties like Gaydos have even come up with a plausible theory for how C. pneumoniae could do that damage: here鈥檚 how.

Free ride

快猫短视频s studying atherosclerosis know that the build-up of atheroma is not just a crude furring-up, like sludge in a pipe, but inflammation and thickening due to an immune defence mechanism gone wrong. The trouble starts when the endothelium, the tissue lining the artery, is irritated by low-density lipoproteins (the so-called bad cholesterol), tobacco components and other substances. Immune cells called macrophages rush to the site of the injury, where they become bloated with lipoproteins. Next, they are drawn out of the blood and accumulate in the vessel wall, forming the fatty streaks that are the first signs of damage. As the damage grows, the inflammation worsens, more macrophages are attracted to the scene and the cells lining the blood vessel proliferate and grow fibrous. According to the theory, an infection of C. pneumoniae in a blood vessel could help to fuel that process, or even start the whole thing off.

Inflammation and chronic infection are hallmarks of the chlamydia family. For instance, C. trachomatis inflames and scars the fallopian tubes. Put crudely, C. pneumoniae may be inflicting similar damage to the artery wall. For that to happen, however, it has to get from the lungs to the coronary arteries.

The crux of the theory, says Gaydos, is that C. pneumoniae hitches a ride on macrophages that pass through the lung鈥檚 alveoli, enter the bloodstream, and then get pulled into the vessel wall at the site of an injury. Macrophages, after all, are all-purpose scavengers that eat not only low-density lipoproteins but also pathogens. Once C. pneumoniae gets into the vessel wall, the infection would cause more inflammation and pull more macrophages into the tissue, leading to a downward spiral of damage.

So appealing is this theory that believers, agnostics and even professed unbelievers like Hammerschlag, are all investing time and effort to test it in the laboratory. Hammerschlag鈥檚 team is infecting mice that are naturally prone to atherosclerosis with chlamydia to see whether they develop the condition earlier than uninfected animals. Grayston鈥檚 lab has begun similar experiments with rabbits. And Gaydos has managed to infect human endothelial cells with C. pneumoniae in the lab, while others have infected human macrophages. Most recently, Gaydos tested whether a human macrophage can carry the bacterium into the smooth muscle cells below the lining of the artery鈥攚hich would lend strong support to the C. pneumoniae-heart disease hypothesis. She won鈥檛, however, divulge the results just yet: her colleagues will have to wait for the Vienna meeting.

The cardiovascular research establishment, meanwhile, remains largely unconvinced. For those who are prepared to entertain the chlamydia hypothesis, such as Gaydos, this is no surprise. 鈥淭he gastroenterologists were the last to believe the Helicobacter evidence,鈥� she says. So there is a long slog ahead: the final answer will come only through long-term studies in people and animals. In the meantime, Hammerschlag鈥檚 advice is strictly practical: 鈥淒on鈥檛 take your prophylactic erythromycin just yet.鈥�

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Off to a bad start

THE idea that an infection might trigger coronary heart disease first sent David Barker, an epidemiologist at the University of Southampton, on a train of inquiry that eventually led to a very different notion. He now believes that coronary heart disease is caused by undernourishment before birth and during infancy.

Like other researchers, Barker was puzzled by the sharp geographical variations in CHD in Britain. People who live in heart disease hotspots, such as northwest England, are twice as likely to die of it as people living in, say, London, even when differences in smoking and diet are taken into account.

When Barker and his colleagues looked at health records, they noticed that the areas where death rates from CHD are high today match those where death rates in newborn babies were high 60 or more years ago. This suggested that the factors threatening the babies also raises the risk of CHD in later life.

The team became even more convinced of a connection when they found that underweight babies were more likely to grow up to have high blood pressure, high cholesterol levels, and diabetes鈥攁ll factors that up the risk of CHD. In addition, the left ventricle of the hearts of both adults who were very small as babies and adults with CHD, tend to have a thick wall, suggesting that undernourishment in early life alters the heart鈥檚 structure in a way that predisposes a person to heart disease. Barker speculates that the undernourished fetus 鈥渞eprograms鈥� various physiological mechanisms to maximise its chances of short-term survival, at the expense of the long term.

Shoring up Barker鈥檚 theory is evidence that the correlation between slow infant growth and adult CHD holds true for all social classes, and is independent of adult lifestyle, although eating a high-fat diet can bump up the risk even more. These relationships could even explain the overall trends in CHD in the West, says Barker. People who reached middle age in the 1930-50s were far more likely to have started life undernourished and then to have switched to a relatively affluent diet, a history that could account for their soaring death rates from CHD. Better nutrition in the 1920s led to a decline in death rates from the 1960s onwards.

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Coughs and sneezes spread diseases, but which ones鈥�

THE hunt for an infectious culprit is spreading to a wide range of diseases that we tend to assume cannot be caught from a fellow passenger who sneezes on a crowded bus. A company in Seattle, called PathoGenesis, is hoping to find some of the infectious agents, using a technique called representational difference analysis (RDA) which compares the RNA in diseased and healthy tissues, subtracts all the sequences common to both, and analyses what鈥檚 left. Any RNA found only in diseased tissue may hold clues to the presence of a possible infectious agent. And because RDA鈥攗nlike established techniques for hunting down the RNA and DNA of microbes, such as polymerase chain reaction鈥攕tarts out with no particular 鈥渃andidates鈥� in mind it does not bias, or limit, the results.

PathoGenesis is coy about the particular diseases it has its eye on, but here are some of the microorganisms under suspicion, and some of the diseases researchers suspect are triggered by unknown infectious agents.

Microbes under suspicion but not yet proved guilty:

• Chlamydia pneumoniae: a link with coronary heart disease, and possibly stroke and asthma?
• Cytomegalovirus, a member of the herpes virus family, which rarely harms healthy adults but can cause organ damage in infants: a link with heart disease too?
• Borna disease virus, an RNA virus that affects the nervous systems of mammals and birds: a possible link with schizophrenia?

Diseases that might be triggered by an unknown infectious agent:

• Rheumatoid arthritis and other types of arthritic disease
• Sarcoidosis (a disease in which nodules form in the lungs and other organs)
• Multiple sclerosis
• Irritable bowel syndrome