3 June 2010

Can you catch a heart attack?

Cosmos Online
Could bacteria and viruses be causing everything from heart disease and cancer to diabetes and even obesity? Many studies are discovering evidence for pathogens as a possible cause for many chronic illnesses.
Heart attack

Credit: Corbis

A winning smile can melt even the coldest of hearts, they say. But your smile might do more than just cheer people up: it may also reveal how healthy you are … or whether you’re a step away from a heart attack.

Research suggests that bacterial scum in and around poorly cleaned teeth, if allowed to build over many years, not only causes infections in the mouth but could also cause serious health problems elsewhere in the body.

It could lead to a build-up of fatty deposits in blood vessels and, eventually, a heart attack or stroke. It now seems that all that brushing and flossing could actually save your life.

Heart disease is just one of a growing number of diseases, long thought to have predominantly genetic or environmental causes, which may in fact have a pathogen such as a bacterium or virus at their root. New studies of these micro-organisms are reshaping our fundamental understanding of how illnesses as diverse as heart disease, cancer and even obesity may arise.

The diverse microbial soup that resides inside our body, and its health implications, has been studied for more than 30 years by medical scientist Trevor Marshall of Murdoch University in Perth, Western Australia.

He has advanced a controversial hypothesis that bacterial infections can lead to certain chronic diseases, including many kinds of inflammations caused when the body attacks its own tissues.

The premise is based on the idea that our body is a ‘superorganism’, comprised of 10% human and 90% bacterial cells. Human saliva, for example, contains hundreds of different species of bacteria, as do our digestive tracts.

In 5% of cases, samples from prosthetic hip joints removed from patients revealed highly unusual bacteria more usually found in hydrothermal vent communities.

But how do these hitchhikers cause chronic disease? Marshall believes that molecules produced by bacteria directly interfere with genes responsible for producing immune system proteins.

“Take, for example, a gene called PTPM 22 that is associated with lupus, rheumatoid arthritis and diabetes [all autoimmune diseases],” he says. “If the body senses the presence of bacteria known as mycobacteria, it upscales production of PTPM 22 ,which then drives these particular diseases.”

Researchers from the University of Buffalo in New York, USA, reported findings at the International Association for Dental Research General Session in April 2009 that heart attacks are more common in people with both a greater number and a greater variety of species of bacteria in their mouths.

“This does not come as a surprise, if the body cannot control bacterial levels then disease mechanisms take over,” says Marshall.

As the world’s number one killer, the causes and risk factors of heart disease have been widely studied. According to the World Health Organisation, each year almost 20 million people worldwide die of cardiovascular disease, a term that covers heart attacks, strokes and other blood vessel disorders.

In Australia alone, they resulted in 34% of all deaths in 2006. The upshot is that, with figures such as these, even a small improvement to our knowledge about the underlying causes could make a very big difference to the number of people affected by it.

Pauline Ford at the University of Queensland in Brisbane is studying the links between periodontal infections of the teeth and gums and heart disease. She believes that adapting our lifestyles to lessen the risk is a very effective strategy; but it is important to clarify exactly what those risks are.

“Up to 50% of people with heart disease have none of the conventional risk factors – for example high blood pressure or high cholesterol – so we need to look into other causes such as infection,” says Ford.

“We propose that many infections, especially those that do not give rise to obvious symptoms such as gum disease, have the potential to add to the total burden of infection and inflammation carried by an individual, resulting in heart problems.”

The causes and drivers of heart disease are many and vary from one individual to the next. However, there are some underlying mechanisms that are accepted as fundamental to the nature of the disease.

Atherosclerosis is one. This is the accumulation of fatty deposits inside the artery, which harden and narrow the vessel, restricting blood flow. This could lead to a major traffic jam in the body’s interconnected highways of blood vessels, leading to a heart attack or stroke, and often death.

The precise cause of this narrowing and eventual gridlock within the arteries is the issue. A growing body of researchers argue that long-term infection is partly to blame. But can bacteria really break a person’s heart? Or, for that matter, can bacteria and viruses destroy joints, trigger cancer or make the body accumulate fat?

Most micro-organisms enter the body through the mouth and respiratory tract. Chlamydia pneumoniae causes pneumonia; Helicobacter pylori causes stomach ulcers; and Porphyromonas gingivalis causes periodontal or gum disease.

Ford believes that over the long term, having a low-grade, persistent gum infection is a risk factor for atherosclerosis. “The longer the infection is allowed to exist – and with gum disease this can be for many years – then the larger this burden becomes,” she says.

The level of inflammation isn’t enough to make someone appear obviously sick, but is enough to change the linings of blood vessels and make them more susceptible to the lesions of atherosclerosis.

“The longer the heightened inflammation exists, the more these lesions may progress. It may not be until the lesion ruptures and the person suffers a heart attack or stroke that we realise this process was even occurring,” Ford says.

The first links between gum and heart disease were made in 1979. An expert review of 15 of the most significant studies published by the American Heart Journal in 2007 showed that both the prevalence and incidence of heart disease are significantly increased in patients with gum disease.

It concluded that periodontal infection may be a risk factor for heart disease, and that further studies were needed to confirm the findings.

Recognising infections of the mouth as an indicator of overall health is nothing new. Clinicians have examined the tongue and oral cavity for telltale signs of ill health for centuries.

With periodontal disease, the gums appear swollen and bleed during brushing due to damage to the tissues and bones that anchor the teeth. In the worst cases, sufferers may lose their teeth.

Some scientists suggest that bacteria migrate into the circulatory system, giving them the opportunity to cause infection elsewhere in the body and/or stimulating an immune reaction.

Alternatively, inflammatory chemicals and messengers known as cytokines produced locally at the site of gum infection may pass into circulation.

Ford and her colleagues argue that the progression of atherosclerosis via bacterial infection could be due to the body’s immune response to proteins known as heat-shock proteins (HSP). These are produced by both the invading bacteria and the person infected.

HSPs are produced by cells within the blood vessel wall when the body is under stress. But they’re also produced widely across nature and differ very little between bacteria and humans. Consequently, the immune system cannot distinguish between the HSPs produced by bacteria and those made by its own body.

“After prolonged exposure to bacterial HSPs, the immune system ends up attacking the body’s own human HSPs in the blood vessel lining. T cells which react to both human and bacterial heat-shock proteins have also been found in the arteries and peripheral blood of patients with atherosclerosis,” says Ford.

She notes that the HSP response probably works in tandem with other more established risk factors for atherosclerosis.

For example, high blood cholesterol levels might enhance levels of HSPs in blood vessels, causing a double-whammy effect: the increased production of the proteins would amplify the immune response, potentially turning lesions caused by cholesterol into severe and irreversible atherosclerosis.

Another possible explanation for the link is the direct infection of artery walls by bacteria in the blood. Porphyromonas gingivalis has been located inside atherosclerotic plaques or lesions themselves, says Ford.

Few experts claim to have conclusive proof of an association between oral hygiene and heart disease and it remains a hypothesis that is widely accepted by dentists but not so often by doctors.

However, investigators from Columbia University Medical Centre, in New York City, found that one in four heart disease sufferers they studied who did not have the traditional risk factors did have a personal history of gum disease and higher levels of an inflammatory molecule.

Lori Mosca, professor of medicine at Columbia University College of Physicians and Surgeons led the study which was published in the American Journal of Cardiology. in 2008. She says that it is impossible to tell from this study alone whether poor oral health causes heart diseases, but it may potentially be the latest weapon in identifying individuals at risk.

“If it is determined that periodontal disease is a causal factor in the development of cardiovascular disease, then preventing or treating periodontal disease could be a key mechanism through which cardiovascular disease risk can =be reduced,” she explains.

Jeremy Pearson, a biologist who specialises in the circulatory system and is based at the British Heart Foundation in London, agrees that the evidence in favour of an association between periodontal disease and heart disease is good, but notes that the increase in risk is relatively small at around 20%.

He also doubts the direct action of bacteria in causing narrowing of the arteries. “This means that brushing your teeth is important, but you could reduce your risk of heart disease more effectively by making other lifestyle changes such as reducing your cholesterol levels or stopping smoking; which can increase risk of heart problems by up to five times,” he says.

So the precise mechanism by which microbes might trigger heart disease requires further investigation, but how do research findings stack up for other chronic diseases supposedly caused by bacteria and viruses?

Much of the evidence to date is epidemiological or looks at the relationship between various microbes and chronic diseases in large populations.

Enteroviruses, which cause vomiting and diarrhoea, have been found in the pancreases of people with type 1 diabetes. That disease, which prevents the pancreas from producing enough insulin to remove sugar from the blood, typically develops in youth and is increasing at an alarming rate – the charity Diabetes U.K. predicts a 70% increase in prevalence by 2020.

There is an inherited element to the disease, but studies on twins show that if one of them has the disease there is only a 40% chance that the other develop it too, hinting at an important role for environmental factors.

“This is the first large-scale evidence of viral involvement in diabetes type 1,” says Noel Morgan from the Peninsula Medical School in Plymouth, England, who co-authored the study.

“It may be that in some patients, persistent, long-term infection alters the functioning of the insulin-producing cells so the immune system wrongly recognises them as foreign and attacks them.”

Some other studies have suggested that gum disease contributes to the development of type 2 diabetes, which strikes people later in life than type 1.

Could pathogens even be making us fat? Researchers at Louisiana State University in Baton Rouge reported in the International Journal of Obesity in 2007 that a type of common cold virus known as adenovirus-36 (Ad-36) may have a role in some cases of obesity.

This virus is usually only associated with eye and respiratory infections, but in fat tissue in the laboratory it has been shown to transform adult stem cells (cells which have yet to specialise as a particular cell type) into fat cells. Stem cells not exposed to the virus remained unchanged.

In 2008 the same team identified a gene in Ad-36 that appears to be involved in fat accumulation in infected animals.

A different group at Washington University in St Louis reported in Nature in 2006 that the variety of gut bacteria are different in obese humans and mice compared to individuals of normal weight. Further research has shown that when obesity is decreased in humans through a low-calorie diet, the relative proportion of microbes corrects itself.

And the list of infectious agents continues with an old favourite: Epstein-Barr virus. This is most commonly associated with glandular fever but is also credited with sometimes sending the immune systems into overdrive, potentially leading to another autoimmune disorder related to inflammation: multiple sclerosis.

“Susceptibility to MS is inherited but environmental insults such as viral infections are thought to trigger the disease. Epstein-Barr virus is one of the leading candidates,” says Jan Lünemann, a researcher at Rockefeller University in New York City who was part of the team that conducted the research.

Another team, from the Harvard School of Public Health in Boston, has found that antibodies to the Epstein-Barr virus were present in some individuals with MS up to 20 years before the onset of disease symptoms.

Interestingly, by age 40, 95% of people have been exposed to Epstein-Barr virus sometime during their lives, but they don’t all develop MS. So which individuals are most likely to succumb to chronic disease as a result of infection?

Murdoch University’s Trevor Marshall believes that susceptibility is determined by the microbes already accumulated in your body and whether you are taking immunosuppressive drugs or other substances known to weaken the immune system, such as vitamin D.

“It depends on the number and nature of the infections we are exposed to over the course of our lives and which microbial genomes accumulate, incrementally shutting down the [innate] immune system,” he says.

“Mutations caused by microbes directly or by interference with DNA repair machinery will encourage development of disease. But we have no definitive answer yet.”

After heart disease, cancer is the world’s next biggest killer, with the most recent WHO figures attributing 7.4 million deaths to cancers each year worldwide. Cancer is often associated with tobacco smoke, chemicals or radiation, all of which trigger damage to a cell’s DNA and uncontrollable growth into a tumour.

But viruses such as human papilloma (HPV) and hepatitis B (HBV) are widely recognised and documented as major causes of cancer worldwide. Most developed countries screen women between their twenties and sixties for the presence of HPV and now run vaccination programs for teenage girls, using a vaccine developed by Ian Frazer of the University of Queensland.

Meanwhile, HBV is now recognised as so virulent and widespread that over 164 countries around the world vaccinate children against HBV, which can cause liver cancer if left untreated.

And the list of cancers with a potential link to a viral or bacterial source is growing. In 2008, researchers from Imperial College, London, found that gum disease was linked with a higher chance of lung, kidney, pancreatic and blood cancers.

By examining health records and questionnaires of nearly 50,000 men, researchers found that men with a history of periodontal disease had a 14% higher chance of cancer compared to those with no history of gum disease. Notably, leukaemias rose by 30%.

Study author Dominique Michaud and his team suggest that a particular immune system impairment common to both heart disease and cancers could be a common cause in both diseases – but the nature of this impairment remains unknown.

Similarly, Andrew Grulich and colleagues at the University of New South Wales in Sydney have found a possible link between an impaired immune system and various cancers. Published in The Lancet, their study looked at two groups of patients: those with HIV/AIDS and kidney transplant patients, both of whom have suppressed immune systems.

“What we found is that the extent of cancer occurrences in these two populations was very similar. Both had increased rates in a wide variety of cancers. Both groups were at a significant risk of developing 20 of the 28 cancers studied, including cancer of the liver, stomach, cervix, eye, lip, mouth and penis,” he says.

Many of the cancers found in this study reflect a known infectious cause. For example, HPV is linked to cervix, anus, vulva/vagina, penis and mouth or throat cancers. “Our results also demonstrate that it is not just infection, but the [lack of] control of infection by the immune system in immune-deficient conditions, that is related to cancer risk. Our research raises a question about whether milder immune deficiency might also be responsible for variations in cancer risk,” adds Grulich.

Like heart disease and gum infections, the link between viruses and breast cancer divides the scientific community. The Grulich study showed no sign of breast cancer in patients with suppressed immunity. However, other groups are building the case for a viral trigger to a disease, which kills more women than any other.

Mouse Mammary Tumour Virus (MMTV) has been under investigation as a cause for breast cancer since the 1930s.

In the mid-1990s, Beatriz Pogo, professor of medicine, haematology and medical oncology from the Mount Sinai School of Medicine in New York, detected sequences of the MMTV virus in 38% of breast tumour tissue samples – but not in healthy breast tissue or other kinds of tumours.

To prove a link, researchers also have to show that the virus can infect certain tissues and turn cells malignant.

“Until now, few viruses have been proven to cause cancer in humans, but we are close to demonstrating malignant transformation both in-vitro and in-vivo breast cancer,” she says.

“It is also important to demonstrate the presence of antibodies to the virus in women with positive tumours, to show that they were antibody negative before and became positive after infection and cancer development.”

To progress the work into the link between MMTV and breast cancer, scientists need to discover where and how the viral DNA slots itself into the human DNA. Stanislav Indik, a researcher from the University of Veterinary Medicine in Vienna, Austria, explains that, in 2007, his group showed for the first time that MMTV can infect and replicate in human cells.

“We created a cell line from healthy human breast tissue and infected it in the lab. I believe this can happen in real life, although we are not sure how exactly at the moment,” he says.

Indik explains that their next step is to detect the actual locations where MMTV fits into the human DNA. If these sites show viral DNA – directly followed by human DNA – then the scientists will have located where the virus sits in the human genome.

That bacteria and viruses might be the cause of many diverse human diseases represents a sea change in scientific thinking. Marshall discusses the paradigm shift that accompanies the principles behind this research.

“Essentially, it is most important to look at the similarities between diseases rather than the differences: clinicians are trained to look at different symptoms, scientists look at similarities. Thirty years ago, I noticed that patients being treated for infertility also often had arthritis or diabetes, so it was hard to believe that these conditions were discrete.”

Research into the links between infection and chronic disease has been progressing slowly for nearly 30 years, so is it just an ongoing medical research exercise or will it ever have an impact on clinical practice?

Though many medics and dentists sit on opposites sides of the fence regarding the link between gum infection and heart disease, some doctors are starting to warm to the idea that good oral health is important to stave off a range of diseases.

Mark Kearney is a cardiologist at the University of Leeds in England. He says that gum disease is a risk factor that warrants further investigation. “I believe atherosclerosis is likely to be caused by systemic inflammation which damages the vessel walls,” he says.

“But don’t forget, this isn’t the first time bacterial infections have been related to heart problems. Endocarditis – an infection which causes inflammation of the heart valves – has a well-established link with streptococcal infection originating in the mouth.”

Only 10 years ago, patients having heart valves replaced due to endocarditis had to have teeth removed to control the infection before the procedure.

“As for cardiologists taking practical measures to control periodontal infection in relation to heart disease – I would need some more convincing first,” adds Kearney.

In the 20th century, improved hygiene and antibiotics helped consign many infectious diseases to something you worry about when visiting poor parts of the world. Now, after a long period of disinterest in the West, infectious diseases are once again a hot area of research, and it seems there’s a lot more to viruses and bacteria than we gave them credit for.

Whether we will ever see cardiologists examining teeth for indicators of heart disease, or dentists referring to cardiologists on the strength of gum disease, everyone agrees: what goes on in your mouth is a lot more interesting to science than it used to be.

Becky McCall is a freelance science writer based in London, England.


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