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1-The Alarming Increase in Ticks and Tick-Borne Diseases

July 26, 2014

http://articles.extension.org/pages/71091/the-alarming-increase-in-ticks-and-tick-borne-diseases

A voluminous 2011 Institute of Medicine report, Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases, calls the lowly tick “the Swiss Army knife of disease vectors...able to host greater variety of disease agents than any other arthropod.”

As the report’s title indicates, there’s a lot scientists still don’t know about ticks and the complex interactions between them, their hosts, the habitats they occupy, and the pathogens they carry.

But we do know that both tick populations and the diseases spread by ticks have risen dramatically in the past couple of decades, and continue to rise.

The diseases ticks can transmit

Many tick-borne diseases are serious or life-altering, even life-threatening.

 New diseases, or at least newly-discovered diseases ticks can spread, seem to crop up with increasing frequency, such as the recently named Heartland virus, the deer-tick Powassan virus, and a Lyme-like disease spread by the bacterium Borellia miyamotoi.

 Ticks and tick-borne diseases occur in every state in the U.S., though some have become endemic, even epidemic, in certain regions. Ticks may even carry and simultaneously transmit two or more infections, complicating diagnosis and treatment of these illnesses.

 Some diseases may be more common than official reports suggest. For example, about 30,000 cases of Lyme disease, the most common tick-transmitted disease, are reported each year, but studies conducted by the Centers for Disease Control and Prevention (CDC) suggest the number is closer to 300,000.  

 A few tick facts

 The recent discovery of a common tick ancestor suggests that ticks and their unique blood-feeding capabilities emerged around 250 million years ago, with the two tick families (hard and soft) diverging and the species within them evolving from about 240 to 230 million years ago.

 Long before humans appeared on the scene, ticks had already evolved the astonishingly complex assortment of anatomical, physiological, and biochemical tools that enable them to disable or bypass the protective defenses of their hosts and allow them to feed efficiently and exclusively on blood.

 Today, almost 900 species of ticks live in terrestrial regions all over the world, according to Jerome Goddard, a medical entomologist with Mississippi State University, an expert on the ecology and epidemiology of tick-borne diseases.

 Of the many tick species, Goddard says five are most significant in human and/or veterinary medicine in the U.S.:

 The black-legged tick, which can carry and transmit Lyme disease, anaplasmosis, babesiosis, and a Powassan virus called "deer-tick disease."

The American dog tick, which can transmit Rocky Mountain spotted fever and tularemia. It also can carry a neurotoxin that causes a condition called “tick paralysis.”

The Lone Star tick, may transmit ehrlichiosis, Southern tick-associated rash illness (STARI), Heartland virus, a mysterious illness called “red meat disease,” bobcat fever (which can be fatal to house cats), and tularemia.

The Gulf Coast tick, which can spread a form of bacterial illness similar to Rocky Mountain spotted fever.

The brown dog tick, a serious pest of dogs, can complete its entire life cycle indoors. It thrives in kennels and homes, and may cause canine ehrlichiosis and canine babesiosis. It also transmits Rocky Mountain spotted fever.

Dogs and cats, as well as livestock and some wildlife species, are susceptible to tick bites and a number of tick-borne illnesses. Check with your vet to see which ones are prevalent in your area.

 Life cycle of most hard ticks

 The Ixodid (“hard”) ticks that may carry and transmit most of the pathogens that cause human disease have long and complex life cycles.

 For example, adult female black-legged ticks (Ixodes scapularis) lay their eggs, often several thousand at a time, in the spring. In mid-August the eggs hatch into minute, six-legged larvae, which immediately begin seeking their first blood meal, generally finding it from a small rodent, sometimes from a bird that brushes by.

 “The current thinking on Lyme disease is that the larval tick picks up the bacterium causing Lyme disease, Borrelia burgdorferi, when they take their blood meal from small rodents, such as white-footed mice,"  says Jim Dill, extension entomologist and pest management specialist with the University of Maine. "The scientific community is uncertain as to whether or not the bacterium is transmitted ‘transovarially' to the eggs and, hence, resulting larvae would hatch infected."  

 Infected mice, chipmunks, and birds don’t become sick themselves with the diseases they carry, says Dill, so they serve as reservoirs of these pathogens, passing them along to the next tick that bites them.

 The six-legged larvae feed for a few days, then drop to the ground. They lie dormant over winter, digesting their meal and using their energy to transform into eight-legged nymphs about the size of a poppy seed. These nymphs emerge in late spring-early summer and begin seeking their second meal, usually from a larger animal such as a deer, a dog, or a human.

 “Nymphs, which feed actively in late spring and early summer, are the stage most dangerous for humans, mainly because they’re so hard to see,” says Dill, who has contracted Lyme disease twice himself.

 After feeding, the nymph drops off and molts into an adult, which must find another blood meal before mating to begin the cycle again.

 Co-evolution of ticks and pathogens

 Over tens of millions of years, many microorganisms have co-evolved with ticks, exploiting the sophisticated ecological niche of the tick salivary system. Ticks have developed an ingenious two-way system that sends concentrated nutrients from the blood meal into the tick’s gut in one direction, while returning the excess fluid--along with any pathogens living in the tick’s saliva--back into the body of the host. The host’s disabled immune response may help the injected disease-causing organisms off to a good start.

  Why ticks have been so successful

 Ticks inhabit many terrestrial regions around the world, but flourish best in warm, humid climates because of their need for moisture and their lengthy life cycle, which is inhibited by extreme cold.

 What's the secret to their success in colonizing the globe?

 Goddard answers quickly: “They have few predators. Some birds, including guinea fowl and backyard chickens, will eat them, but they don’t do much to control tick populations.”

 Adds Dill, “Ticks are so adaptable. For example, the black-legged tick has adapted to a wide variety of small rodents, birds, and large mammal hosts.”

 Entomologists also say that other factors such as shifts in populations of hosts and reservoir animals, changes to local landscapes, human settlements encroaching on wildlife habitats and into areas of abundant tick populations, are playing a role.

 Although drying out is the primary cause of tick mortality, the tick’s salivary system has another extraordinary property that allows a fasting tick to survive months without drinking. It uses its forelegs to detect a source of higher humidity, then moves to that spot and secretes a substance from its mouth that’s able to absorb water vapor from the air.

 When the substance is saturated, the tick pulls it back, where it evaporates and helps rehydrate the tick’s body.

 Finally, Goddard says, “You can’t escape the conclusion that climate change is playing a role in the explosion of tick-borne illnesses, when you see tropical ticks and diseases expanding their range northward, even up mountainsides.”

 Why the dramatic spike in ticks and tick-borne illnesses?

 Given the co-evolution of ticks and the pathogens they carry, humans and other animals have probably always suffered from tick-transmitted diseases.

 Scientists at Oregon State University have found a tick preserved in amber believed to be about 15 million years old, containing a species of Borrelia bacteria similar to the one that causes Lyme disease today. The same team has also found amber-encased tick fossils dating back around 100 million years in Myanmar, containing bacterial cells similar to those that cause Rocky Mountain spotted fever.

 But why the big spike in recent decades?

 “There are simply more opportunities for human/tick encounters,” says Goddard. “A primary reason is the increase in the population of the white-tailed deer [preferred host of adult black-legged ticks]. He notes that many states encourage an abundant deer population to attract hunters and wildlife enthusiasts.

 “In 1910, the U.S. had a deer population of around 300,000. A century later, there were four million of them.”

 Protecting yourself

 Vigorous ongoing research around the world aims at developing vaccines that could protect humans and other animals against the pathogens ticks transmit or against the ticks themselves.

 But self-protection currently remains the best line of defense against tick bites and any tick-borne illness.

 Protecting yourself and people you care for from tick bites begins with understanding the life cycles and habitats of disease-causing ticks in your area, either staying out of those areas or taking protective measures when venturing into tick terrain.  

 Dill suggests, “Wear light-colored clothing and long pants tucked into your socks. Use a repellent containing either DEET or picaridin that lists ticks on the label.”

 “You can also spray permethrin insecticide on your clothing, or buy clothing already treated with the pesticide. They call permethrin a repellent, but it actually kills ticks,” Dill says.

 The Environmental Protection Agency has an interactive site on tick and insect repellents that allows you to find a specific product that will work for you and your outdoor activities. The agency has also just unveiled a new labeling scheme to indicate how many hours a product will repel mosquitoes, ticks or both.

 Dill, who’s twice contracted Lyme disease, suggests a head-to-toe tick check after coming from a wooded or grassy area, especially if you live in an area where ticks and tick-borne illnesses are endemic. Take pains to check inside and around your ears, scalp, and around the hairline, inside the navel, behind the knees, between the toes, and in the groin and armpits. Have a loved one check your back, or use a large mirror in a well-lit space.

 Don’t undress near sleeping or sitting areas of your home. Check your clothing for loose ticks before you hang it up or toss it into the laundry basket. Even hot-water washing won’t kill ticks, only drying at high temperatures.

 2- A Changing Environment and the Increasing Prevalence of Celiac Disease

http://www.celiac.nih.gov/prevalence.aspx

Research studies in the United States and Europe show that celiac disease is significantly more common now than it was a few generations ago. Research by Joseph Murray, M.D., professor of medicine at the Mayo Clinic in Rochester, MN, and colleagues showed that this shift reflects an actual increase in prevalence, not merely a new awareness of the disease and more accurate diagnostic tools. Murray and colleagues’ research compared blood samples collected 50 years ago from more than 9,000 young adults, mostly men, at Warren Air Force Base in Wyoming with current samples from age-matched men. The investigators found that celiac disease is four times more common today than a half-century ago. The increase cannot be a result of changes in the genetic factors that underlie celiac disease, Murray explained. “Of course, human genetics will change in response to the environment, but that change is extremely slow. It’s far more probable that the increase is due to an environmental change, and the most likely factor is a change involving the grain in our diets,” Murray said. “Consumption of wheat has increased steadily over the past 50 years, but it still is less than what it was a century ago, so the issue is not simple consumption,” Murray noted. “It more likely involves the wheat itself, which has undergone extensive hybridization as a crop and undergoes dramatic changes during processing that involves oxidizers, new methods of yeasting, and other chemical processes. We have no idea what effect these changes may have on the immune system.”

A second environmental factor that may be contributing to the increase in celiac disease is what is known as the “hygiene hypothesis,” explained Murray. This theory proposes that the developing immune system has to be stimulated by exposure to infectious agents, bacteria, or parasites in order to develop properly. An increasingly clean environment reduces the number of factors that challenge and stimulate the developing immune system, making infants and children more susceptible to immune disorders and allergic diseases. The hygiene hypothesis may account, in part, for the increases observed not only in celiac disease, but in other allergies and immune disorders. “Diet and hygiene both may play a role in the increase. There no doubt are multiple environmental factors that interact to trigger the onset in people who are genetically predisposed,” Murray said. “The increasing prevalence makes it more important that health care providers and patients are alert to the possibility of celiac disease.”

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Page last updated September 24, 2014

3- Global cancer rates could increase by 50% to 15 million by 2020

http://www.who.int/mediacentre/news/releases/2003/pr27/en/

World Cancer Report provides clear evidence that action on smoking, diet and infections can prevent one third of cancers, another third can be cured

GENEVA, 3 APRIL 2003 - Cancer rates could further increase by 50% to 15 million new cases in the year 2020, according to the World Cancer Report, the most comprehensive global examination of the disease to date. However, the report also provides clear evidence that healthy lifestyles and public health action by governments and health practitioners could stem this trend, and prevent as many as one third of cancers worldwide.

In the year 2000, malignant tumours were responsible for 12 per cent of the nearly 56 million deaths worldwide from all causes. In many countries, more than a quarter of deaths are attributable to cancer. In 2000, 5.3 million men and 4.7 million women developed a malignant tumour and altogether 6.2 million died from the disease. The report also reveals that cancer has emerged as a major public health problem in developing countries, matching its effect in industrialized nations.

“The World Cancer Report tells us that cancer rates are set to increase at an alarming rate globally. We can make a difference by taking action today. We have the opportunity to stem this increase. This report calls on Governments, health practitioners and the general public to take urgent action. Action now can prevent one third of cancers, cure another third, and provide good, palliative care to the remaining third who need it, "said Dr. Paul Kleihues, Director of the International Agency for Research on Cancer (IARC) and co-editor of the World Cancer Report.

The World Cancer Report is a concise manual describing the global burden, the causes of cancer, major types of malignancies, early detection and treatment. The 351-page global report is issued by IARC, which is part of the World Health Organization (WHO).

Dr Gro Harlem Brundtland, Director-General of WHO, states: “The report provides a basis for public health action and assists us in our goal to reduce the morbidity and mortality from cancer, and to improve the quality of life of cancer patients and their families, everywhere in the world,”

Examples of areas where action can make a difference to stemming the increase of cancer rates and preventing a third of cases are:

Reduction of tobacco consumption. It remains the most important avoidable cancer risk. In the 20th century, approximately 100 million people died world-wide from tobacco-associated diseases

A healthy lifestyle and diet can help. Frequent consumption of fruit and vegetables and physical activity can make a difference.

Early detection through screening, particularly for cervical and breast cancers, allow for prevention and successful cure.

The predicted sharp increase in new cases – from 10 million new cases globally in 2000, to 15 million in 2020 - will mainly be due to steadily ageing populations in both developed and developing countries and also to current trends in smoking prevalence and the growing adoption of unhealthy lifestyles.

“Governments, physicians, and health educators at all levels could do much more to help people change their behaviour to avoid preventable cancers,” says Bernard W. Stewart, Ph.D., co-editor of the report, Director of Cancer Services, and Professor, Faculty of Medicine, University of New South Wales, Australia. “If the knowledge, technology and control strategies outlined in the World Cancer Report were applied globally, we would make major advances in preventing and treating cancers over the next twenty years and beyond.”

From a global perspective, there is strong justification for focusing cancer prevention activities particularly on two main cancer-causing factors - tobacco and diet. We also need to continue efforts to curb infections which cause cancers,” said Dr Rafael Bengoa, Director, Management of Non-communicable disease at WHO. “These factors were responsible for 43 per cent of all cancer deaths in 2000, that is 2.7 million fatalities, and 40 per cent of all new cases, that is four million new cancer cases.”

As part of an effort to stem this trend, WHO is engaged in efforts to stem both tobacco use, and to improve diet, nutrition and physical activity. Tobacco consumption remains the most important avoidable cancer risk. The report reviews and recommends a number of strategies to reduce global tobacco consumption, requiring the coordinated involvement of government and community health organizations, health care professionals and individuals. The groundbreaking public health treaty - the Framework Convention on Tobacco Control - which the Member States of WHO have agreed to submit to the World Health Assembly in May 2003, represents a powerful tool to ensure that such strategies are implemented.

WHO is also engaged in preparing a Global Strategy on Diet, Physical Activity and Health, under a May 2002 mandate from Member States to address the growing global burden of chronic diseases, including cancers, cardiovascular diseases, diabetes and obesity. WHO is consulting widely with Member States, other UN agencies, the private sector and civil society on the strategy, which will be presented to the World Health Assembly in May 2004. The strategy will contain recommendations for governments on nutrition and physical activity goals and population-based interventions to reduce the prevalence of chronic disease including cancer.

The World Cancer Report – The major findings

Tobacco, the case for primary prevention

Tobacco consumption remains the most important avoidable cancer risk. In the 20th century, approximately 100 million people died world-wide from tobacco-associated diseases (cancer, chronic lung disease, cardiovascular disease and stroke). Half of regular smokers are killed by the habit. One quarter of smokers will die prematurely during middle age (35 to 69 years).

The lung cancer risk for regular smokers as compared to non-smokers (relative risk, RR) is between 20 and 30 fold. In countries with a high smoking prevalence and where many women have smoked cigarettes throughout adult life, roughly 90 per cent of lung cancers in both men and women are attributable to cigarette smoking. For bladder and renal pelvis, the RR is five-six but this means that more than 50 per cent of cases are caused by smoking.

The RR for cancers of the oral cavity, oral cavity, pharynx, larynx and squamous cell carcinoma of the oesophagus is greater than six, and three-four for carcinomas of the pancreas. These risk estimates are higher than previously estimated and unfortunately, additional cancer sites with a RR of two-three have been identified as being associated with tobacco smoking, including cancers of the stomach, liver, uterine cervix, kidney (renal cell carcinoma) nasal cavities and sinuses, esophagus (adenocarcinoma) and myeloid leukaemia.

Involuntary (passive) tobacco smoke is carcinogenic and may increase the lung cancer risk by 20 per cent. There is currently no evidence that smoking causes breast, prostate or endometrial cancer of the uterus.

The deadly smoking habit is particularly worrying in Central and Eastern Europe and many developing and newly industrialized countries. The tendency of youth around the world to start smoking at younger and younger ages will predispose them to substantial risks in later life.

While it is best never to start smoking, epidemiological evidence supports the enormous benefits of cessation. The greatest reduction in the number of cancer deaths within the next several decades will be due to those who stop the habit. The greatest effect results from stopping smoking in the early 30s, but a very impressive risk reduction of more than 60per cent is obtained even when the habit is quit after the age of 50 years.

The report reviews and recommends a number of strategies to reduce global tobacco consumption, requiring the coordinated involvement of government and community health organizations, health care professionals and individuals. The groundbreaking public health treaty - the Framework Convention on Tobacco Control represents a powerful tool to ensure that such strategies are implemented.

Infection and cancer: intervention is key

In developing countries, up to 23 per cent of malignancies are caused by infectious agents, including hepatitis B and C virus (liver cancer), human papillomaviruses (cervical and ano-genital cancers), and Helicobacter pylori (stomach cancer). In developed countries, cancers caused by chronic infections only amount to approximately 8 per cent of all malignancies. This discrepancy is particularly evident for cervical cancer. In developed countries with an excellent public health infrastructure and a high compliance of women, early cytological detection of cervical cancer (PAP smear) has led to an impressive reduction of mortality while in other world regions, including Central America, South East Africa and India, incidence and mortality rates are still very high. Today, more than 80 per cent of all cervical cancer deaths occur in developing countries.

Vaccinations could be key to preventing these cancers. HBV vaccination has already been shown to prevent liver cancer in high-incidence countries and it is likely that human papillomavirus (HPV) vaccination will become a reality in 3 to 5 years.

In the gastro-intestinal tract (GIT), any chronic tissue damage with necrosis and regeneration carries an in creased cancer risk, e.g. consumption of very hot beverages (squamous cell carcinoma of the esophagus), gastro-oesophageal reflux (adenocarcinoma of the esophagus), chronic gastritis induced by H. pylori infection (stomach cancer), Crohn’s disease (cancer of the small intestines) and ulcerative colitis (colon cancer).

Poverty, affluence and the global burden of cancer

In developed countries, the probability of being diagnosed with cancer is more than twice as high as in developing countries. However, in rich countries, some 50 per cent of cancer patients die of the disease, while in developing countries, 80 per cent of cancer victims already have late-stage incurable tumors when they are diagnosed, pointing to the need for much better detection programs.

The main reasons for the greater cancer burden of affluent societies are the earlier onset of the tobacco epidemic, the earlier exposure to occupational carcinogens, and the Western nutrition and lifestyle. However, with increasing wealth and industrialization, many countries undergo rapid lifestyle changes that will greatly increase their future disease burden.

“Once considered a “Western” disease, the Report highlights that more than 50 per cent of the world’s cancer burden, in terms of both numbers of cases and deaths, already occurs in developing countries. “Cancer has emerged as a major public health problem in developing countries for the first time, matching its effect in industrialized nations. This is a global problem, and it’s growing. But, we can take steps to slow this growth,” says Paul Kleihues, MD, Director of IARC and co-editor of the World Cancer Report.

The Western lifestyle and its health risks

The Western lifestyle is characterized by a highly caloric diet, rich in fat, refined carbohydrates and animal protein, combined with low physical activity, resulting in an overall energy imbalance. It is associated with a multitude of disease conditions, including obesity, diabetes, cardiovascular disease, arterial hypertension and cancer.

Malignancies typical for affluent societies are cancers of the breast, colon/rectum, uterus (endometrial carcinoma), gallbladder, kidney and adenocarcinoma of the oesophagus. Prostate cancer is also strongly related to the Western lifestyle, but there is an additional ethnic component; black people appear to be at a greater risk than whites and the latter at higher risk than Asian populations. Similar lifestyles are associated with a similar tumour burden. Since they have a common cause, these neoplasms typically go together. There is no region in the world that has a high incidence of breast cancer without a concurrent colon cancer burden.

Obesity is spreading epidemically throughout the world. It visualizes a chronic energy imbalance and is an independent predictor of an increased cancer risk, particularly for carcinomas of the uterine endometrium, kidney and gall bladder.

Together with the independent Expert Report on diet and chronic disease, released in March 2003 by WHO and FAO (Food and Agriculture Organization) the World Cancer Report provides policymakers with the latest information on which to base advice.

Nutrition and cancer – the good news

Stomach cancer is among the most common malignancies worldwide, with some 870,000 cases every year, and 650,000 deaths. About 60 per cent of cases occur in developing countries, with the highest incidence rates coming in Eastern Asia, the Andean regions of South America and Eastern Europe. The good news is that stomach cancer is declining world-wide, in some regions almost dramatically. In Switzerland and neighbouring European countries, the mortality fell by 60 per cent within one generation. If this trend continues, stomach cancer may in some world regions become a rare disease during the next 30 years. The main reason for this welcome development is the invention of the refrigerator, allowing fish and meat preservation without salting. The drop in incidence and mortality rates is therefore particularly impressive in Nordic countries in which fish consumption is traditionally high, e.g. Iceland. In populations that still prefer salty food, e.g. Portugal and Brazil (salted cod, bacalao), Japan and Korea (salted pickles and salad), stomach cancer rates are still high but have also started to decline significantly. An additional factor contributing to this trend is the availability in many countries of fresh fruit and vegetables throughout the year.

Cancer prevention: a healthy diet can help!

Epidemiological studies indicate that the frequent consumption of fruit and vegetables may reduce the risk of developing cancers of epithelial origin, including carcinomas of the pharynx, larynx, lung, oesophagus, stomach, colon and cervix. Recent data from the European Prospective Investigation into Cancer and Nutrition (EPIC), suggests that a daily consumption of 500 grams (1.1. lbs.) of fruits and vegetables can decrease incidence of cancers of the digestive tract by up to 25 per cent.

The report also says that given the multi-faceted impact of diet on cancer, many countries should encourage consumption of locally produced vegetables, fruit and agricultural products, and avoid the adoption of Western style dietary habits. IARC says that such actions would have health benefits beyond cancer, since other common non-communicable diseases, notably cardiovascular disease and diabetes, share the same lifestyle-related risk factors.

Early detection – the best strategy second to primary prevention The best possible prevention against cancer remains the avoidance of exposure to cancer-causing agents: this is called primary prevention (eg tobacco, industrial carcinogens, etc).

There is sound evidence that the recent decline in cancer mortality observed in several countries is to a significant extent due to early detection. Responsible for this success are not only improvements in imaging (mammography, magnetic resonance (MR) and computed tomography (CT) imaging), but also a higher degree of disease awareness and educational programmes on typical early symptoms. Most successful so far has been the early detection of cervical cancer by cytology and of breast cancer by mammography. A recent analysis by an IARC Working Group concluded that under trial conditions, mammography screening may reduce breast cancer mortality by 25-30 per cent and that in nation-wide screening programmes a reduction by 20 per cent appears feasible. There is also emerging evidence that prostate cancer screening by assessment of serum PSA levels may result in lower mortality rates but management of early lesions is still very invasive. For colon cancer, colonoscopy is considered the gold standard although its application in population-based screening programmes would require considerable medical resources.

Cancer control strategies

The aim of cancer control is a reduction in both the incidence of the disease and the associated morbidity and mortality, as well as improved life for cancer patients and their families. In addition to substantial opportunities for primary prevention, the World Cancer Report also emphasizes the potential of early detection, treatment and palliative care. It urges all countries to establish comprehensive national cancer control programmes, aimed at reducing the incidence of the disease and improving the quality of life for cancer patients and their families. In developing countries in particular, where a large proportion of cancers are detected late in the course of the disease, efforts to achieve earlier diagnosis and delivery of adequate palliative care and pain relief deserve urgent attention.

Cancer by the Numbers

Lung cancer is the most common cancer worldwide, accounting for 1.2 million new cases annually; followed by cancer of the breast, just over 1 million cases; colorectal, 940,000; stomach, 870,000; liver, 560,000; cervical, 470,000; esophageal, 410,000; head and neck, 390,000; bladder, 330,000; malignant non-Hodgkin lymphomas, 290,000; leukemia, 250,000; prostate and testicular, 250,000; pancreatic, 216,000; ovarian, 190,000; kidney, 190,000; endometrial, 188,000; nervous system, 175,000; melanoma, 133,000; thyroid, 123,000; pharynx, 65,000; and Hodgkin disease, 62,000 cases.

The three leading cancer killers are different than the three most common forms, with lung cancer responsible for 17.8 per cent of all cancer deaths, stomach, 10.4 per cent and liver, 8.8 per cent.

Industrial nations with the highest overall cancer rates include: U.S.A, Italy, Australia, Germany, The Netherlands, Canada and France. Developing countries with the lowest cancer were in Northern Africa Southern and Eastern Asia. (A complete list of cancer rates by countries can be found at http://www-dep.iarc.fr/.

Lung cancer in women

Lung cancer strikes 900,000 men and 330,000 women yearly. Among men, smoking causes more than 80 per cent of lung cancer cases. In women, smoking is the cause of 45 per cent of all lung cancer worldwide, but more than 70 per cent in North America and Northern Europe. In both men and women, the incidence of lung cancer is low before age 40, and increases up to age 70 or 75.

The rise in female smoking prevalence is a major public health concern. In the US, more women die from smoking-induced lung cancer than from breast cancer and in some Nordic countries, including Iceland and Denmark, female lung cancer deaths have begun to outnumber male tobacco victims. Considering that in several European countries up to 50 per cent of young women are now regular smokers, this will cause a disease burden that significantly reduces women’s health in decades to come.

Colon cancer

Cancers of the colon and rectum are rare in developing countries, but are the second most frequent malignancy in affluent societies. More than 940,000 cases occur annually worldwide, and nearly 500,000 die from it each year.

A major cause is a diet rich in fat, refined carbohydrates and animal protein, combined with low physical activity. Genetic susceptibility appears to be involved in less than five per cent of cases. Epidemiological studies suggest that risk can be reduced by decreasing meat consumption (particularly processed meat) and increasing the intake of vegetables and fruit. Migrant populations rapidly reach the higher level of risk of the adopted country, another sign that environmental factors play a major role.

Colonocopy is the most reliable means for early detection. Progressively improved diagnosis and treatment has resulted in a five-year survival rate of 50 per cent.

Key statements

Tobacco use is the major preventable cause of cancer in the world.

Molecular genome research will reveal a tremendous amount of information on cancer but it is not clear how easy these discoveries will translate into actual lives saved and may well be restricted to rare cancers.

As developing countries succeed in achieving lifestyles similar to Europe, North America, Australia, New Zealand and Japan, they will also encounter much higher cancer rates, particularly cancers of the breast, colon, prostate and uterus (endometrial carcinoma).

Researchers will demonstrate that successful behavioral changes in tobacco, alcohol and diet will prevent far more cancers than the elimination of toxins such as industrial pollution, car exhaust and dioxins;

The Pap smear for cervical cancer is the single best cancer screening procedure. The medical community must develop a wide spectrum of tests for other cancers and are now evaluating many procedures to determine if they are effective and practical;

The major differences of cancer between the sexes are the predominance in males with lung, liver, stomach, esophageal and bladder cancer; for the most part, these differences derive from patterns of exposure to the causes of the cancers, to a smaller extent they reflect intrinsic gender differences in susceptibility.

More than one million cases of breast cancer occur worldwide annually, with some 580,000 cases occurring in developed countries (>300/100,000 population per year) and the remainder in developing countries (usually 50% in the prevalence of adolescent obesity since the late 1970s.7 In terms of physical activity levels, there was no change in the proportion of US high school students engaged in regular vigorous physical activity from 1991 through 1995, and there has been a decrease in the participation of high school students in daily physical education classes.8 This backslide in the health status of US teenagers has far-reaching consequences for future overall morbidity and mortality in general and for cardiovascular disease in particular.

Worldwide, cardiovascular disease is also assuming an increasing role as a major cause of morbidity and mortality. Between 1990 and 2020, the proportion of worldwide deaths from cardiovascular disease is projected to increase from 28.9% to 36.3%.9 Moreover, in terms of number of years of life lost, it is projected that cardiovascular disease will jump in ranking from fourth to first, while as a cause of premature death and disability, it will rise from fifth to first. The projected increases in the importance of cardiovascular disease worldwide are related principally to two trends in developing countries: (1) the eradication of malnutrition and infectious diseases as primary causes of death, which is allowing for an aging of the population, and (2) marked increases in cigarette smoking.10

Thus, the enormous and increasing burden of cardiovascular disease among those in middle and older age in developed countries, the alarming trends in cardiovascular risk profiles of young people, and the emerging pandemic of cardiovascular disease all underscore the crucial need to redouble both policy and research efforts in treatment and prevention.

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Contributions of Different Types of Evidence

It is crucial to consider the totality of evidence for any question because each research discipline has its unique strengths and limitations (Table 1⇓). Basic research has the unique strength of precision, meaning the ability to achieve virtually complete control of all exposures, including both environment and genetics. Further, basic research provides the scientific underpinnings for all applied research in humans. Thus, basic research provides unique and crucial information concerning disease mechanisms. However, basic research also has the disadvantage of potential lack of relevance to free-living humans because of such differences as species specificity, dose, and routes of administration of exposures. Thus, the results from basic research may differ so greatly from those that apply to free-living humans as to render them of questionable direct relevance. The inability to predict the applicability of findings from a particular species of animals to humans was underscored by John Cairns, who wrote, “Who could have guessed thatHomo sapiens would share with the humble guinea pig the unenviable distinction of being incapable of synthesizing ascorbic acid, or share with armadillos a susceptibility to the bacterium that causes leprosy, or that intestinal cancer usually occurs in the large intestine of humans and the small intestine of sheep?”11

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Table 1.Sources of Evidence in Identifying Risk Factors for Cardiovascular Disease

While the findings from basic research may be limited in their ability to provide a reliable quantitative estimate of human disease risk, the precision possible in such research provides unique and crucial information that is of great value in setting priorities for studies in free-living humans to test their relevance.

Epidemiology, on the other hand, because it is based directly on observations of free-living humans, has the unique advantage of relevance. However, for this very reason, epidemiological studies have the potential disadvantage of imprecision. Indeed, in contrast to basic research, epidemiology is crude and inexact because observations in free-living humans can never take place under the controlled conditions possible in the laboratory. Nonetheless, epidemiology contributes essential information to a totality of evidence, which then can support a judgment of a cause-effect relationship.

Making such a judgment involves several steps, the first being to establish whether there is in fact a valid statistical association. To conclude that an association is valid, alternative explanations for the finding must be ruled out, including the potential roles of chance, bias, and confounding. If a valid statistical association is present, the question then becomes, Is it one of cause and effect? To render this judgment, the totality of evidence from all sources must be considered, with particular attention given to the strength of the association, the consistency of the evidence from different studies, and the existence of a plausible biological mechanism to explain the findings.

Epidemiological studies can be either descriptive (case reports and case series, correlational studies, and cross-sectional surveys) or analytical (observational case-control or cohort studies and randomized trials). Descriptive studies are useful primarily for the formulation of hypotheses; analytical studies, for hypothesis testing. Whereas observational analytical studies are often criticized because of their potential for bias—case-control studies in the selection of individuals into the study and in their recall of prior events and cohort studies in losses to follow-up—many exposure-disease relationships have been well established from observational evidence.12

There are two chief strengths of observational evidence. The first relates to the evaluation of exposures that require long duration; the second is the ability to detect moderate to large effects, which can be roughly translated to mean those effects with relative risks >1.5. With respect to the evaluation of exposures that require long duration, one example of the strength of observational studies is the evaluation of the relationship between blood pressure and risk of myocardial infarction (MI). Basic research had suggested mechanisms for a benefit of blood pressure lowering on risks of stroke and MI, and observational studies had consistently demonstrated a statistically significant 40% to 45% increased risk of stroke and a 25% to 30% increase in risk of MI associated with a prolonged 6 mm Hg difference in diastolic blood pressure.13 In contrast, although individual randomized trials of pharmacological therapy of mild to moderate hypertension indicated that blood pressure lowering by 6 mm Hg resulted in a comparable 40% decrease in risk of stroke, there was a far smaller and less certain benefit on MI than that suggested by the observational evidence. The apparent inconsistency remained even after the availability of results from 14 individual randomized trials of drug therapy in 37 000 subjects. This led some to conclude that treatment of hypertension did not benefit the risk of subsequent MI. However, a comprehensive overview, or meta-analysis, of the trials demonstrated that a decrease of 6 mm Hg in diastolic blood pressure significantly reduced stroke by 42% and MI by a smaller but statistically significant 14%.14 A subsequent meta-analysis, which included several additional trials, demonstrated the reduction in risk of MI to be 16%.15 The 14% to 16% reduction in risk of MI seen in the randomized trials over 3 to 5 years of treatment was about half the 28% reduction one would predict from the results of observational studies of blood pressure lowering over decades. This discrepancy may well have been due to chance but also could have been due to the fact that stroke risk immediately decreases after blood pressure levels are lowered, whereas MI risk may be affected by prolonged effects of hypertension on the more chronic processes of atherogenesis and thus would require far longer than the usual 3 to 5 years of treatment in trials to observe the full impact. Thus, basic research and observational studies with long durations of exposure have been crucial components of the totality of evidence concerning the relationship of blood pressure lowering with risk of MI.

The second strength of observational studies lies in evaluating associations in which the relative risk is moderate to large in size—relative risks >1.5. In this regard, observational evidence has provided both the necessary and sufficient information on which to judge a cause and effect relationship for a large number of important questions of clinical importance and public health significance. Chief among these has been the health effects of cigarette smoking. Starting in 1950 with case-control studies by Doll and Hill in the United Kingdom16 and Wynder and Graham in the United States,17 observational epidemiological studies established a clear association between smoking and lung cancer, with risks among long-term smokers about 20 times greater than those of nonsmokers. Based on their observational evidence, Doll and Hill judged smoking to be a cause of lung cancer years before there was any clear understanding of the actual mechanism of alterations in DNA by initiators or promoters of cancer. In 1964 the US Surgeon General also judged smoking a definite cause of this disease, still years before the biological mechanism was clearly understood.18 Thus, although basic research is crucial in identifying mechanisms that explain causal or preventive factors, direct answers to the questions of whether particular exposures are associated with risks of disease may derive from straightforward observation of what actually happens in free-living human populations.

With regard to smoking and CHD, the finding that current cigarette smokers have about an 80% increased risk has been consistently demonstrated over the last 30 years by different investigators in a large number of case-control and cohort studies involving millions of person-years of observation.19 It is interesting that smoking was not judged to be a cause of CHD until far later than the judgment that it caused lung cancer. Part of this related to the lack of a clear biological mechanism. However, another reason related directly to a limitation in interpreting the findings from any observational study; namely, that as the relative risk gets smaller, there is increasing concern that some factor other than the exposure being studied may explain all or at least part of the findings. For example, cigarette smokers may share other characteristics or lifestyle practices that independently affect their risk of CHD. Information can be collected on any potential confounding variables known to the investigator and then used in the data analysis to adjust for any impact of these factors. However, there can be no adjustment for the effects of unmeasured or unmeasurable confounding variables.

When a large effect is seen, such as with smoking and lung cancer, the amount of uncontrolled confounding may affect the magnitude of the relative risk estimate, making it, for example, as high as 22 or as low as 18. It is unlikely, however, that complete control of confounding would materially change the conclusion that there is a strong positive association between smoking and lung cancer. Even in the case of current smoking and CHD, although uncontrolled confounding may mean that the true relative risk is as small as 1.6 or as large as 2.0 instead of the 1.8 most consistently seen in observational studies, that range of uncertainty does not materially affect the conclusion that current cigarette smoking increases the risk of CHD. On the other hand, when the most plausible effect size is only 20% to 40%, as is the case with most promising interventions today, a small amount of uncontrolled confounding could mean the difference between a relative risk of 0.8, indicating a 20% decreased risk; 1.0, indicating no effect; or 1.2, indicating a 20% increased risk.

A recent example that illustrates some of these issues is the possible role of antioxidant vitamins in prevention of cardiovascular disease and cancer. Basic research has provided evidence of plausible mechanisms for antioxidant vitamins in the prevention of these diseases. As regards cardiovascular disease, antioxidant vitamins can inhibit the oxidation and/or uptake of LDL cholesterol, the particularly atherogenic form of cholesterol. In addition to descriptive studies, a large number of analytical observational studies have examined the antioxidant hypothesis. Several large-scale prospective cohort studies have found decreased cardiovascular disease risks among subjects with higher intake of antioxidant vitamins, either through diet or supplements.20

The problem with all these studies, however, is that the decreased risk seen in those with the highest intake or blood levels tended to be modest in size, on the order of 20% to 40%. Such small to moderate benefits may have a tremendous public health impact for a common and serious disease, but they are statistically very difficult to demonstrate reliably. In the case of antioxidant vitamins, it may be, for example, that those with greater intake of antioxidant vitamins share other dietary or nondietary lifestyle practices that account for all or some of the observed association with antioxidant vitamins. Adjustments can be made for known confounding variables for which data are collected. However, observational studies are unable to control for the potential effects of confounding variables not collected or known to the investigators. In searches for modest-sized effects, the amount of uncontrolled confounding may be as large as the most likely effect.

For all these reasons, only randomized trials of sufficient sample size and duration of treatment and follow-up are able to detect reliably small to moderate treatment effects. If the trials are large enough, the randomization process will, on average, evenly distribute among treatment groups known and unknown confounding variables. In addition, very large trials will be necessary to avoid the possible uninformative null result of no benefit when in fact a modest-sized benefit truly exists. For many, if not most, hypotheses, randomized trials are neither necessary nor desirable. For detecting small to moderate effects, however, they represent the most reliable research design strategy.

With respect to antioxident vitamins, four large-scale randomized trials of beta-carotene supplementation have been completed.21 22 23 24 Overall, their results for CHD have not supported the promising evidence that accumulated from basic research, descriptive studies, and analytical observational investigations. The results certainly do not preclude the possibility that some benefit may yet emerge for antioxidants. Indeed, several trials ongoing trials are evaluating antioxidants in both primary and secondary prevention of cardiovascular disease, and the evidence remains particularly promising for vitamin E. However, with respect to beta-carotene supplementation, the data currently available from completed trials indicate no overall benefits on cardiovascular disease among well-nourished populations. These data suggest that the findings from observational studies of possible benefits may indeed have reflected some influence of confounding variables associated with beta-carotene intake that explain all or some of the decreased risks of cardiovascular disease among those with high intake levels. The findings also raise the possibility that the antiatherogenic mechanisms for beta-carotene described in basic research may not have direct relevance to the effects of supplementation with this antioxidant on human disease risk.

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Risk Factors: Current Knowledge and Future Directions for Research

Genetics certainly plays a role in cardiovascular disease risk, but there is also clear evidence from international differences in disease rates and migrant studies that cardiovascular disease must have important environmental determinants. Studies of Japanese migrants have been particularly informative in this regard. The Ni-Hon-San study25 tracked the health experience of Japanese men living in the Japanese cities of Hiroshima and Nagasaki, men of Japanese ancestry living in the Honolulu area of Hawaii, and Japanese men in the San Francisco Bay area in California. The study revealed substantial differences in CHD mortality rates between the three groups, with men in Japan having the lowest rates, those in Hawaii having somewhat higher rates, and men in the San Francisco area having the highest rates.25 Thus, in these findings among genetically similar populations, migration and the adoption of lifestyle practices of the local population were accompanied by a substantial increase in CHD death rates.

With respect to the identification of modifiable risk factors, during the 20th century, the contributions of basic research, clinical investigation, observational epidemiology, and randomized trials have yielded a totality of evidence on which it has been possible to judge proof beyond a reasonable doubt that modification of several factors decreases risks of cardiovascular disease (Table 2⇓). These include cigarette smoking, elevated cholesterol levels, and hypertension. Other factors, such as obesity, physical inactivity, and diabetes, are clearly associated with increased risks of cardiovascular disease, but the evidence currently is less clear that modification of these factors yields decreased risks of CHD.26 For all of these risk factors, however, public policy recommendations have been issued by such major health organizations and institutions as the AHA, the NHLBI, and the National Institute for Neurological Diseases and Stroke, and efforts must be redoubled to achieve wider implementation of these existing recommendations.

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Table 2.Causal and Preventive Risk Factors for Cardiovascular Disease

Although substantial gains can be achieved through control or elimination of established risk factors for cardiovascular disease, it is also important to consider that in data from the United Kingdom Heart Disease Prevention Project and other cohorts, approximately half of all patients suffering a CHD event have no established risk factors.27 This situation has prompted the investigation of promising interventions that could have widespread utility in treatment and primary prevention of cardiovascular disease. These include antioxidant vitamins, low-dose aspirin, and hormone replacement therapy in women.

With respect to low-dose aspirin, in 1971, Sir John Vane, who later received the Nobel prize for his work, demonstrated that in platelets, small amounts of aspirin irreversibly acetylate the active site of cyclooxygenase, which is required for the production of thromboxane A2, a powerful promoter of platelet aggregation.28Higher doses provided no additional benefit, and it has been postulated that far higher doses might reverse this tendency because of activation of vessel wall enzymes. A totality of evidence is now available, which includes randomized trials in secondary prevention or treatment among patients with a wide range of occlusive vascular diseases, in the acute phase of evolving MI, and in primary prevention among apparently healthy individuals.29 For secondary prevention30 31and acute evolving MI,32 there is conclusive evidence in both men and women of net benefits of aspirin on subsequent MI, stroke, and overall vascular death. Thus, extensions of the existing labeling indications for aspirin are clearly needed to include virtually all patients who have suffered an occlusive vascular disease event. Wider use of aspirin in these conditions would avoid 10 000 premature deaths each year in the United States. For primary prevention, there is conclusive evidence in men of benefit on risk of a first MI,33 but the data are currently inconclusive on stroke and vascular death. Further, there is a possible increase in hemorrhagic stroke. Thus, while we await the results of primary prevention trials, such as the ongoing Women’s Health Study among 40 000 female health professionals,34 the decision to prescribe aspirin in primary prevention must be an individual clinical judgment between the healthcare provider and each of his or her patients. Such a judgment must take into account the patient’s risk profile, the side effects of aspirin, and its clear benefit in reducing the risk of a first MI. In addition, the use of aspirin should always be as an adjunct, not alternative, to control or elimination of the established risk factors for cardiovascular disease.

With respect to hormone replacement therapy, basic research has provided plausible mechanisms for benefits, including improvements in lipid profile, and observational epidemiological studies have indicated that women who self-select for hormone treatment have decreased risks of CHD.35 Women using hormones also experience reductions in menopausal symptoms and osteoporosis but increased risks of uterine cancer with unopposed estrogen and increases in gallbladder disease and breast cancer.36

However, it is important to note that all these findings have been made in case-control and observational cohort studies, so the self-selection by women and their healthcare providers of hormone replacement therapy may be responsible, in part or perhaps even wholly, for the observed associations. Thus, despite the fact that MI kills about eight times as many women as breast cancer, whether the benefits of hormone replacement therapy outweigh the risks for all women is not yet clear. Several ongoing randomized trials, the largest of which is the Women’s Health Initiative, will provide the necessary direct evidence for this question.

In addition to these promising hypotheses, we are also markedly increasing our understanding of the multifactorial causes of CHD. These genetic and environmental determinants include both atherogenic and thrombotic factors. For acute MI, the primary underlying cause is atherosclerosis, whereas the proximate cause of virtually all cases is thrombosis.37 In this context, many potential new markers of CHD are under investigation (Table 3⇓).38 These include the primarily atherogenic marker homocysteine, the primarily thrombotic marker fibrinogen, and other primarily inflammatory markers, such as C-reactive protein.

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Table 3.Potential New Risk Factors for Cardiovascular Disease

With respect to possible atherogenic markers, there is increasing interest in the possible role of homocysteine in cardiovascular disease.39 Basic research has shown methionine to be an essential amino acid that depends on several enzymes related to B12 and folate metabolism for conversion from homocysteine. In clinical studies, individuals with homocystinuria develop very premature onset of severe CHD. Regardless of the source of the defect, all patients with elevated levels of homocysteine have increased risks of CHD.

Several observational epidemiological studies, both case-control and cohort, have shown that those with higher levels of homocysteine tend to have increased risks of CHD. This emerging totality of evidence has raised the question of whether reducing levels of homocysteine would, in turn, decrease risks of cardiovascular disease.

In the Physicians’ Health Study, the significant predictors of higher homocysteine are age, the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotype, and current smoking; whereas predictors of lower homocysteine levels are current multivitamin use and higher intakes of folate.40 These and other data have raised the hypothesis that folate may lower homocysteine and decrease risks of MI. Only randomized trials can address this issue definitively. Currently, one secondary prevention trial of folate is ongoing among patients with prior stroke, and several other trials have been proposed.

With respect to thrombotic markers, >40 years ago, plasma fibrinogen levels were demonstrated to be higher among patients with acute thrombosis. The first prospective study to show an association between fibrinogen levels and subsequent cardiovascular disease risk was the Swedish Gothenborg Heart Study in 1984.41 In the Northwick Park Heart Study in the United Kingdom, fibrinogen and factor VII appeared to be as effective as total cholesterol in predicting future risk of CHD.42 It remains unclear, however, whether elevated fibrinogen level is a cause or consequence of atherosclerosis.38

Whether modification of fibrinogen levels will lower risks is now being evaluated in several secondary prevention trials.43 With regard to the fibrinogen hypothesis, however, because the agents being tested all have potential benefits on other markers of risk, including lipids, the results, even if positive, may be difficult to interpret. Nonetheless, randomized trials to determine the ability of an agent to modify a thrombotic factor and to assess whether such modification in fact decreases risks of subsequent occlusive events will be a crucial component in translational research on any of the new markers from being a focus of research investigation to clinical and public health relevance.

C-reactive protein, a marker of systemic inflammation, has recently been evaluated as a potential risk factor for cardiovascular disease in the Physicians’ Health Study, a randomized trial of aspirin and beta-carotene in the prevention of cardiovascular disease and cancer. In a prospective nested case-control analysis using baseline blood specimens, increased levels of C-reactive protein were associated with increased risks of subsequent MI and ischemic stroke.44 The use of aspirin was associated with significant reductions in the risk of MI (55.7%, P=.02) among men in the highest quartile but with only a small, nonsignificant reduction among those in the lowest quartile (13.9%, P=.77). These findings on MI raise the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.

With respect to inflammation and cardiovascular disease, proinflammatory cytokines raise markers such as C-reactive protein. Proinflammatory cytokines also increase coagulation45 and cause an unfavorable lipid profile of a peculiar form, with decreased cholesterol, decreased HDL cholesterol, and increased triglycerides.46 It also appears that infection,47 48 smoking,49 diabetes,50 and periodontal disease51 all increase proinflammatory cytokines, whereas aspirin,44nonsteroidal antiinflammatory drugs,52 antioxidants,53 and glucocorticoids54 may decrease proinflammatory cytokines. These complex interrelationships and their possible clinical relevance require further evaluation in basic, clinical, and epidemiological research.

Thus, we are now entering new frontiers of research that have the potential for greatly expanding our understanding of risk factors for cardiovascular disease. In addition to homocysteine and fibrinogen, the promising atherosclerotic and/or thrombotic markers include factor VII, endogenous tissue plasminogen activator, plasminogen activator inhibitor, D-dimer, and lipoprotein(a). From a pathophysiological perspective, further research is needed on the balance between procoagulant factors—such as factor VII, impaired fibrinolysis, tissue plasminogen activator levels, and plasminogen activator inhibitor—and evidence of ongoing clot formation—such as fibrinogen or D-dimer. Potential genetic markers requiring further research include possible predictors of arterial disease, such as the MTHFR genotype, the ACE gene, and angiotensinogen, as well as possible predictors of venous disease, such as the factor V mutation. There is also increasing interest in the relationship of psychosocial factors, socioeconomic status, environmental stresses, and social disparity with cardiovascular disease risk.

The current totality of evidence supports a complex multifactorial model as more plausible than any single genetic marker to predict risk of CHD. Because we are at the early stages of research on all these new fronts, many important questions remain, including whether measurement of these potential new risk factors will complement or overlap with established risk factors. Specifically, the research on these new markers raises three important questions. First, does the assessment of any new marker add to the ability to predict who is at elevated risk over and above the predictive value of established risk factors? Second, are there means of favorably modifying levels of atherosclerotic and/or thrombotic markers? And third, would knowledge of genetic factors affect clinical practice?

With continued research, it seems likely that some environmental factors, including atherosclerotic, thrombotic, and inflammatory markers, as well as genetic factors, may well becomeas routinely measured as part of the assessment of the cardiovascular risk profile of an individual. It seems less likely, however, that such measurements would ever replace our focus on established risk factors.

In that regard, we should not let the perfect be the enemy of the possible. Substantial benefits can still be gained from control or elimination of established cardiovascular risk factors. Specifically, in terms of blood cholesterol, a 10% decrease corresponds to roughly a 30% decrease in risk of CHD.26 With the publication of the Scandinavian Simvastatin Survival Study,55 the West of Scotland Coronary Primary Prevention Study,56 and most recently the Cholesterol and Recurrent Events trial57 in the United States, the totality of evidence now indicates clear benefits of cholesterol lowering by HmG-CoA reductase inhibitors, or statins, on MI, stroke, cardiovascular death, and total mortality.58 For blood pressure, a 6 mm Hg decrease in diastolic pressures >90 mm Hg through pharmacological therapy among those with mild to moderate hypertension results in a 16% decrease in CHD and a 42% decrease in stroke.14 15 Cessation of cigarette smoking yields about a 50% decrease in risk of CHD,19 even among the elderly,59 beginning within months of cessation. The benefits of smoking cessation assume particular importance in light of the epidemic of tobacco use now occurring in developing countries, which will cause a substantial increase in their cardiovascular disease rates during the next several decades.10 Finally, the continuing epidemic of obesity in the United States is perhaps second only to smoking as the leading avoidable cause of all premature deaths.60 61 62

The clear need for more public education concerning the continuing epidemic of cardiovascular disease is reflected in the results of a recent Gallup poll, in which 46% of women perceived breast cancer to be their major health risk, while only 4% believed this to be the case for heart disease.63 The reality, however, is that although 1 in 25 women will die from breast cancer, 1 in 3 will die from heart disease.

Thus, for established risk factors, we clearly must redouble our clinical and public policy efforts. The dividends this will yield are clear and immediate. For the promising newer potential risk factors, we need an increase in the commitment of research funding. From 1985 to 1995, the total NIH budget increased by 31.3%. At the same time, however, NHLBI funding rose by just 4.5%—and the portion allocated for heart disease research actually decreased by 5%.64 We have, in some senses, been victims of our own success, as the remarkable progress made over the past several decades in decreasing mortality from cardiovascular disease has contributed to a widespread misperception that the cardiovascular disease “problem” has been solved.

More than 50 years ago, in the landmark federal report “Science: The Endless Frontier,” presidential adviser Vannevar Bush wrote, “Progress in the war against disease depends on a flow of new scientific knowledge. New products, new industries and more jobs require continuous additions to knowledge . . . and the application of that knowledge to practical purposes. Science provides no panacea for individual, social, and economic ills. But without scientific progress, no amount of achievement in other directions can insure our health, prosperity, and security as a nation in the modern world.”65

Praising the far-reaching effects of Bush’s report, Harvard University president Neil Rudenstine wrote in a recent commentary, “We have pursued this path over the past 50 years, and our nation’s health, prosperity and security have benefitted enormously as a result. . . . [I]n our drive to bring the federal budget closer to balance, we must keep in mind that our short-term choices will have profound long-term effects. . . . In the past 50 years, we have built a research enterprise that is the pride of the world. If we damage it, it will not be easily mended. And, in the long run, it will cost far more to rebuild something that has been allowed to slip into disrepair than to keep a strong and productive enterprise running well.”66

In conclusion, whether we are concerned with cardiovascular disease as basic researchers, healthcare providers, clinical investigators, or epidemiologists and statisticians, it is crucial that we maintain a united front in calling for increased public health efforts to combat the current epidemic in the United States and the emerging pandemic of cardiovascular disease. It is equally critical that a steady flow of funding be ensured for the promising new frontiers of research that will greatly aid our understanding of the causes—and our ability to prevent and treat—cardiovascular disease.

In this vein, the words of Benjamin Franklin seem as important and timely today as at the signing of the Declaration of Independence on July 4, 1776: “We must all hang together, or assuredly we shall all hang separately.”67

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Footnotes

Presented as the Lewis A. Conner Memorial Lecture at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10, 1996.

Copyright © 1998 by American Heart Association

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References

↵Conner LA. The American Heart Journal. Am Heart J. 1925;1:115–116.

CrossRef

↵Statistical Abstract of the United States: 1995. Washington, DC: US Department of Commerce; 1995.

↵Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown & Co; 1987.

↵Total Population Death Rate for CVD, by Age, per 100 000, US, 1979–93. Dallas, Tex: American Heart Association; 1996.

↵Health, United States, 1994. Hyattsville, Md: National Center for Health Statistics; 1995.

↵Johnson LD, Bachman JG, O’Malley PM. Cigarette Smoking Continues to Rise Among American Teenagers in 1996. Ann Arbor, Mich: University of Michigan News and Information Services; December 19, 1996.

↵Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents. Arch Pediatr Adolesc Med. 1995;149:1084–1091.

↵Physical Activity and Health: A Report of the Surgeon General. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1996.

↵Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, Mass: Harvard University Press; 1996.

↵Murray CJL, Lopez AD. The Global Burden of Disease: Summary. Cambridge, Mass: Harvard University Press; 1996.

↵Cairns J. The treatment of diseases and the war against cancer. Sci Am.1985;253:51–59.

Medline

↵Hennekens CH, Buring JE. Observational evidence. In: Warren KS, Mosteller F, eds. Doing More Good than Harm: The Evaluation of Health Care Interventions. Ann N Y Acad Sci. 1993;703:18–24.

Medline

↵MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease, 1: prolonged differences in blood pressure—prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–774.

CrossRefMedline

↵Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease, 2: short-term reductions in blood pressure: overview of randomized drug trials in their epidemiologic context. Lancet. 1990;335:827–838.

CrossRefMedline

↵Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med. 1993;153:578–581.

CrossRefMedline

↵Doll R, Hill AB. Smoking and carcinoma of the lung: preliminary report. BMJ.1950;2:739–748.

↵Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of 684 proved cases. JAMA. 1950;143:329–336.

↵Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DS: US Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control; 1964. PHS publication No. 1103.

↵Hennekens CH, Buring J, Mayrent SL. Smoking and aging in coronary heart disease. In: Bosse R, Rose C, eds. Smoking and Aging. Lexington, Mass: DC Heath; 1984:95–115.

↵Hennekens CH, Gaziano JM, Manson JE, Buring JE. Antioxidant vitamin-cardiovascular disease hypothesis is still promising, but still unproven: the need for randomized trials. Am J Clin Nutr. 1995;62:1337S–1380S.

Abstract/FREE Full Text

↵Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, Yu Y, Liu Bq, Tangrea J, Sun Yh, Liu F, Fraumeni JF, Zhang YH, Li B. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483–1492.

Abstract/FREE Full Text

↵Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035.

CrossRefMedline

↵Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Branhard S, Hammar S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155.

CrossRefMedline

↵Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med.1996;334:1145–1149.

CrossRefMedline

↵Worth RM, Kato H, Rhoads GG, Kagan A, Syme SL. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: mortality. Am J Epidemiol. 1975;102:481–490.

Abstract/FREE Full Text

↵Manson JE, Tosteson H, Ridker PM, Satterfield S, Hebert P, O’Connor GT, Buring JE, Hennekens CH. The primary prevention of myocardial infarction. N Engl J Med. 1992;326:1406–1416.

CrossRefMedline

↵Heller RF, Chinn S, Tunstall Pedoe HD, Rose G. How well can we predict coronary heart disease? Findings in the United Kingdom Heart Disease Prevention Project. BMJ. 1984;288:1409–1411.

↵Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235.

CrossRefMedline

↵Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation. 1989;80:749–756.

FREE Full Text

↵Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged anti-platelet therapy. BMJ. 1988;296:320–332.

↵Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet treatment, I: prevention of vascular death, myocardial infarction and stroke by prolonged antiplatelet therapy in different categories of patients. BMJ. 1994;308:81–106.

Abstract/FREE Full Text

↵ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.1988;2:349–360.

Medline

↵Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989;321:129–135.

CrossRefMedline

↵Buring JE, Hennekens CH, for the Women’s Health Study Research Group. The Women’s Health Study: summary of the study design. J Myocardial Ischemia. 1992;4:27–29.

↵Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N Engl J Med.1991;325:756–762.

CrossRefMedline

↵Rich-Edwards J, Manson JE, Hennekens CH, Buring JE. Primary prevention of coronary heart disease in women. N Engl J Med. 1995;332:1758–1766.

CrossRefMedline

↵Braunwald E. Foreword. In: Fuster V, Verstraete M, eds. Thrombosis and Cardiovascular Disease. Philadelphia, Pa: WB Saunders; 1992.

↵Ridker PM, Hennekens CH. Hemostatic risk factors for coronary heart disease. Circulation. 1991;83:1098–1100.

FREE Full Text

↵Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;7:878–881.

↵Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation. 1996;94:2410–2416.

Abstract/FREE Full Text

↵Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505.

CrossRefMedline

↵Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.Lancet. 1986;2:533–537.

Medline

↵Goldbourt U, Behar S, Reicher-Reiss H, Agmon J, Kaplinsky E, Graff E, Kishon Y, Caspi A, Weisbort J, Mandelzweig L. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Study). Am J Cardiol. 1993;71:909–915.

CrossRefMedline

↵Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.

CrossRefMedline

↵Van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJH, Evenberg AJM, de Groot ER, Jansen J, Gallati H, Büller HR, ten Cate JW, Aarden LA. Elimination of interleukin-6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994;179:1253–1259.

Abstract/FREE Full Text

↵Hardardottir I, Grunfeld C, Feingold KR. Effects of endotoxin and cytokines on lipid metabolism. Curr Opin Lipidol. 1994;5:207–215.

CrossRefMedline

↵Ioamoto GK, Konicel SA. Cytomegalovirus immediate early genes upregulate interleukin-6 gene expression. J Invest Med. 1997;45:175–182.

Medline

↵Örtqvist Å, Hedlund J, Wretling B, Carlström A, Kalin M. Diagnostic and prognostic values of interleukin-6 and C-reactive protein in community-acquired pneumonia. Scand J Infect Dis. 1995;27:457–462.

CrossRefMedline

↵Cohen HJ, Pieper CF, Harris TB, Rao KMK, Currie MS. Associations of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol Med Sci. In press.

↵Hotamisgil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor-necrosis factor-α in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–2415.

↵Takahashi K, Takashiba S, Nagai A, Takigawa M, Myoukai F, Kurihara H, Murayama Y. Assessment of interleukin-6 in the pathogenesis of periodontal disease. J Periodontal Res. 1994;65:147–153.

↵Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848–854.

CrossRefMedline

↵Meydani M, Evans WJ, Handelman G, Biddle L, Fielding RA, Meydani SN, Burrill J, Fiatarone MA, Blumber JB, Cannon JG. Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults. Am J Physiol.1993;264:R992–R998.

Abstract/FREE Full Text

↵DeRijk R, Michelson D, Karp B, Petrides J, Galliven E, Deuster P, Paciotti G, Gold PW, Sternberg EM. Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1β, IL-6, and tumor necrosis factor-α production in humans: high sensitivity of TNF-α and resistance of IL-6. J Clin Endocrinol Metab. 1997;82:2182–2191.

CrossRefMedline

↵Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.

CrossRefMedline

↵Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Primary Prevention Study Group. N Engl J Med. 1995;333:1301–1307.

CrossRefMedline

↵Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009.

CrossRefMedline

↵Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. JAMA. 1997;278:313–321.

CrossRefMedline

↵LaCroix AZ, Lang J, Scherr P, Wallace RB, Cornoni-Huntley J, Berkman L, Curb JD, Evans D, Hennekens CH. Smoking and mortality among older men and women in three communities. N Engl J Med. 1991;324:1619–1625.

CrossRefMedline

↵Manson JE, Stampfer MJ, Hennekens CH, Willett WC. Body weight and longevity: a reassessment. JAMA. 1987;257:353–358.

CrossRefMedline

↵Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE. Body weight and mortality among women. N Engl J Med. 1995;333:677–685.

CrossRefMedline

↵Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B, Speizer FE, Hennekens CH. Weight and weight change in relation to risk of coronary heart disease in women: a 14-year follow-up. JAMA. 1995;273:461–465.

CrossRefMedline

↵Women’s top health risks. U S A Today. May 18, 1995:1-D.

↵Breslow J. Presidential address. Presented at the American Heart Association 69th Scientific Sessions, November 10, 1996, New Orleans, La.

↵Bush V. Science: the endless frontier: a report to the President by Vannevar Bush, director of the Office of Scientific Research and Development. Washington, DC: US Government Printing Office; July 1945.

↵Rudenstine NL. Don’t slash funding for scientific research. The Boston Globe. July 11, 1995.

↵Bartlett J. Famous Quotations: A Collection of Passages, Phrases, and Proverbs Traced to Their Sources in Ancient and Modern Literature. 16th ed. Boston, Mass: Little, Brown and Co; 1992:310.

Hoping this will be helpful,

Rafik

For many diseases, there are treatments that alleviate the symptoms or prevent their onset, but do not cure the disease.

At the mildest end of the disease spectrum is the common cold, caused by a large number of viruses. The symptoms can be alleviated with decongestants, antihistamines and cough suppressants, but there are no drugs currently available that cure the disease by killing the virus or preventing it from replicating.

The effects of cystic fibrosis (CF), a genetic disease caused by various mutations in the CFTR gene, can be alleviated with several treatments that address the symptoms, plus some recently developed drugs that help "cure" the protein defect, although they do not fix the genetic defect. A true cure for CF, or other genetic diseases, would require gene therapy.

HIV/AIDS is an excellent example of the distinction between treatment and cure. HIV infection can be treated with drugs to prevent the onset of AIDS, but it is currently impossible (with one exception) to cure a person of HIV infection because the virus is integrated into the genome of cells, from which it can re-emerge if treatment is discontinued.

In addition to treating and curing diseases, some diseases can be prevented. For example, several infectious diseases (e.g. polio, measles, diphtheria) can be prevented by vaccination. Diseases caused by exposure to harmful substances can be prevented by avoiding the exposure. Most cases of lung cancer, for example, can be prevented by avoiding exposure to the substances that cause it, such as tobacco smoke and asbestos.

Other diseases have become curable thanks to advances in medical science, such as many bacterial infections and hepatitis C. I should also mention surgical intervention, which can cure some diseases. Blindness caused by cataracts, for example, can be cured by replacing the clouded lens with a plastic one. Angina pectoris caused by coronary artery disease can be cured by coronary arterial bypass surgery. A very few diseases have been eradicated, or nearly eradicated, such as smallpox and polio, thanks to immense and costly vaccination campaigns.

Why are there more diseases than there used to be? I don't know that this is true. It may be that medical science has learned to identify diseases that always existed but hadn't been identified. However, there clearly are emerging diseases, especially viral diseases that were previously rare or undiscovered but have become common due to changes in their environment and human behavior. The classic example is HIV/AIDS. There are also diseases that have become more common due to changes in lifestyle, such as obesity and diabetes. And there are diseases that were previously confined to animals but have made the jump to humans recently, such as MERS and SARS.

Thanks a lot for your answers Dr. Rafik and Dr. Adam.