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Time for a Change of Heart?

(This article is also published at CHIS-UK, the Complementary Health Information Service.)

The World Health Organisation estimates that 17 million people every year die of cardiovascular disease (CVD), the collective term for all diseases of the circulatory system including heart attacks and strokes. This total is more than 30% of all deaths worldwide. In developed countries the proportion is even higher. 39% of deaths in the UK in 2002 were attributable to CVD. Globally, coronary heart disease accounts for over 7 million and strokes approaching another 6 million. It’s the world’s number one killer. Since 1990, more people have died from coronary heart disease alone than from any other cause. It’s a global epidemic of monstrous proportions which the WHO described, in their 2003 report Shaping the Future, as “neglected”.

Heart disease

“ Those who merely study and treat the effects of disease are like those who imagine that they can drive away the winter by brushing the snow from the door. It is not the snow that causes winter, but the winter that causes the snow. ”
Paracelsus (Philipus Aurelius Theophrastus Bombastus von Hohenheim) 1493-1541

“ A human being is a part of the whole called by us universe, a part limited in time and space. He experiences himself, his thoughts and feeling as something separated from the rest, a kind of optical delusion of his consciousness. This delusion is a kind of prison for us, restricting us to our personal desires and to affection for a few persons nearest to us. Our task must be to free ourselves from this prison by widening our circle of compassion to embrace all living creatures and the whole of nature in its beauty. ”
Albert Einstein

“ There are two ways to be fooled. One is to believe what isn't true; the other is to refuse to believe what is true. ”
Søren Kierkegaard

“ No question is so difficult to answer as that to which the answer is obvious.”
George Bernard Shaw

“ Sometimes I've believed as many as six impossible things before breakfast. ”
Lewis Carroll

“ Man did not weave the web of life, he is merely a strand in it. Whatever he does to the web, he does to himself. ”
Chief Seattle

“ No man is an island, entire of itself; every man is a piece of the Continent, a part of the maine; if a clod be washed away by the sea, Europe is the less, as well as if a promontory were, as well as if a manor of thy friends or of thine own were; any man's death diminishes me, because I am involved in Mankind; and therefore never send to know for whom the bell tolls; it tolls for thee. ”
John Donne

“ Parts are seen to be in immediate connection, in which their dynamical relationships depend, in an irreducible way, on the state of the whole system (and, indeed, on that of broader systems in which they are contained, extending ultimately and in principle to the entire universe). Thus, one is led to a new notion of unbroken wholeness which denies the classical idea of analysability of the world into separately and independently existing parts ... We have reversed the usual classical notion that the 'independent' elementary parts of the world are the fundamental reality, and that the various systems are merely particular contingent forms and arrangements of these parts. Rather, we say that inseparable quantum interconnectedness of the whole universe is the fundamental reality, and that relatively independently behaving parts are merely particular and contingent forms within this whole. ”
David Bohm and Basil Hiley 'On the intuitive understanding of nonlocality as implied by Quantum Theory'

“ Today we are faced with a challenge that calls for a shift in our thinking, so that humanity stops threatening its life-support system. We are called to assist the Earth to heal her wounds and in the process heal our own. ”
Wangari Maathai

“ How wonderful that we have met with a paradox. Now we have some hope of making progress. ”
Niels Bohr

“ I’m saying that we should trust our intuition. I believe that the principles of universal evolution are revealed to us through intuition. And I think that if we combine our intuition and our reason, we can respond in an evolutionary sound way to our problems. ”
Jonas Salk

“ Intuition is the source of scientific knowledge. ”

Neglected is probably not an adjective that leaps most readily to mind when considering the decades’ worth of person-hours, mountains of research papers, unconscionable sums of money and large numbers of able intellects which have been devoted to the question of what lies behind the global explosion in mortality statistics. It appears to be a disease of civilisation. The main risk factors – smoking, an unhealthy diet, sedentary lifestyle, high alcohol consumption, poor psychosocial wellbeing, obesity, diabetes, raised blood pressure, raised blood cholesterol – are all factors associated with developed, urbanised, industrialised society. Efforts to raise awareness of these risk factors and encourage their reduction, along with developments in the care of those suffering from the disease, appear to have had an impact on the mortality statistics. Since the mid 1960s deaths from heart attack have fallen by more than 50% in many developed countries. It was the leading cause of death in the working population of the US in 1980, but has declined by 26% since and is now in second place behind malignancy.

The neglect the WHO report highlighted refers to the impact of the disease in developing nations. Coronary heart disease is a comparative newcomer on the world stage, but has leapt with alarming alacrity to the top of the mortality charts. International agencies committed to improving global health have tended to overlook heart disease and stroke and many developing countries have no programmes to address these diseases. The WHO estimate that 60% of the global burden of coronary heart disease is now borne by developing countries.

Announcing the study A Race Against Time: the challenge of cardiovascular disease in developing economies published April 2004, co-author Professor Stephen Leeder, Director of the Australian Health Policy Institute, stated “By 2020 there will be a billion people in the world aged over 65. As the global population ages, cardiovascular disease is set to become the leading cause of death and disability worldwide and is threatening to overwhelm health care systems. Developing countries are witnessing the devastation to their workforces that Australia and other western countries experienced 50 years ago.” Professor Stephen MacMahon, Principal Director of Australia’s George Institute for International Health added, “With their fragile health systems, low- to middle-income countries are ill-equipped to deal with the growing burden of diseases such as heart attack and stroke.” This was underlined further by Dr Susan Raymond, also one of the report's co-authors, who said that she had been “surprised, even shocked, by what we found when we looked at the effects of CVD on the productive workforce aged 35-65 years in developing countries. In India, for instance, where 5 million people die of CVD each year, 28% of the deaths occurred among people aged less than 65. This rate of death among younger people exceeds even what we saw in the United States in the 1950s before we started to prevent and treat heart disease and stroke aggressively.”

The global burden of CVD is enormous; and growing. In addition to the dreadful toll in human life, the economic cost of the disease is huge. A 2002 report The economic burden of coronary heart disease in the UK (Liu JLY, Maniadakis N, Gray A and Rayner M, Heart; 88:597-603) estimated the total cost of the disease to the UK economy in 1999 was in excess of £7 billion, of which direct healthcare costs and productivity lost due to mortality were only 35%. This cost was higher than for any other disease similarly analysed. Across Europe as a whole the economic cost of CVD is estimated at some €169 billion (European cardiovascular disease statistics 2005). The WHO calculate that of the total number of healthy years of life lost to disease worldwide, cardiovascular disease accounts for 10% in low- to middle-income countries and 18% in high-income countries. The authors of ‘A Race Against Time’ estimate that the burden for developing countries is set to rise well beyond that of the developed world. “Things are set to get worse. Projections suggest that for ischemic heart disease, a subset of CVD, the mortality for all developing countries between 1990 and 2020 will increase by 120% for women and 137% for men. Predictions for the next two decades include a tripling of ischemic heart disease and stroke mortality in Latin America, the Middle East, and even sub-Saharan Africa, a rate of increase that exceeds that for any other region, except for Asian and Pacific Island countries. By contrast, the increase in CVD deaths in more-developed nations, largely attributable to an expansion of the population of older people at risk, will range between 30% and 60%.” By 2030 they project that the number of healthy years of life lost to CVD will rise by 64% in Brazil, 57% in China and a staggering 95% in India.

Tipping the Scales

Against the sheer enormity of the disease burden, the advances made in developed countries to combat CVD begin to look suspiciously as if they are still only scratching the surface, brushing the snow from the door. Yes, the mortality statistics are trending in the right direction, but it would seem premature to claim that the full extent of the decline has been the result of improved medical interventions and preventive lifestyle changes. As Joel Howell of the University of Michigan writes, “A significant part of the change cannot be fully explained.” (‘Concepts of Heart-Related Diseases’. The Cambridge World History of Human Disease, 1993). In addition, the decline in the incidence of the disease has not been quite so significant as the decline in mortality statistics, and its economic burden is increasing. Over 70 million Americans, 34% of the entire population, are estimated to suffer from CVD at a direct cost to the US economy of $400 billion. “CVD accounted for 38.0 percent of all deaths or 1 of every 2.6 deaths in the United States in 2002. CVD mortality was nearly 60 percent of “total mortality.” This means that of over 2,400,000 deaths from all causes, CVD was listed as a primary or contributing cause on about 1,400,000 death certificates.” (Heart Disease and Stroke Statistics - 2005 update American Heart Association). There is a sense that all the measures employed to counteract the disease are only delaying it – shunting it into old age – rather than having any real impact on its resolution.

And yes, developing countries are rapidly becoming civilised according to the western model, but does the pace and extent of industrialisation match the pace and extent of the explosion in CVD mortality statistics? There seems to be a mismatch somewhere: in scale, in proportion, in pace. Suggestions such as those made by Yusuf and Ôunpuu (Tackling the growing global burden of atherosclerotic cardiovascular diseases Yusuf S, Ôunpuu S. European Journal of Cardiovascular Prevention & Rehabilitation: Volume 10(4) August 2003 pp 236-239) that industrialisation creates a nation of couch potatoes almost overnight don’t hit the right note, and even in combination with other factors such as decreasing childhood mortality, still are somehow unconvincing. (Are we all so accustomed to this disease that we’ve come to expect it as a “normal” development of mid- to old-age?) There’s a niggling feeling of dissatisfaction, as if a crucial piece of the jigsaw puzzle, the very heart of the matter, is still missing. A discomfort that no amount of confident reassurance from researchers and policy-makers can quite overcome.

The disharmony is not just in scale and pace of imputed causes. For a disease that is so focused in its expression on a single body system, so limited in its manifestation to a distinct set of well-defined symptoms, the main risk factors seem a rather nebulous and motley collection of disparate influences that confer a degree of predictability only when considered together. They lack the sharper focus of the disease itself. They can account for around 80% of cases, but that still leaves a large proportion of instances of the disease that don’t seem instantly amenable to an obvious explanation.

Some of the factors – obesity for instance – seem as much a symptom of an underlying malaise as they do a cause. Obesity is simply too prevalent, too insidious in its spread, to be merely a problem of willpower. Since 1991 obesity in the USA has increased 75% (Heart Disease and Stroke Statistics - 2005 update American Heart Association), yet it’s estimated that as much as 50% of American women are on some diet or another at any one time. Something else seems to be going on. Some disruption of metabolism on a more fundamental level. As the authors of ‘A Race Against Time’ point out, “The great unknown now is the effect of rising levels of obesity in many countries where falling CVD mortality has been a feature of recent decades. Will these increases lead to a recrudescence of CVD among younger people? This is a plausible possibility.” And this is not just a problem for developed nations. At the 2002 annual meeting of the American Association for the Advancement of Science (AAAS), University of Rhode Island anthropologist Marquisa LaVelle stated “Changing lifestyles and changing diets have caused an epidemic of obesity around the world.” University of Oxford anthropologist Stanley Ulijazek added “Changes like this, which occur in the course of a generation, are too swift to be based on genetics.” There is something much more pervasive going on. The habits of poor exercise levels and over-eating are catching on at an unprecedented pace.

Could it be that we can’t see the wood for the trees here? Could there possibly be a common factor at work? Something blatantly obvious staring us in the face? Something immense hiding in plain sight that might reveal itself if we just step back from it far enough and ask the right questions?

Assume for a moment that this is a valid proposition, even if it might seem ludicrous – if not downright preposterous – in view of the amount of research already undertaken. What sort of job description could we draw up for this common factor? What criteria would adequately define a match for the patterns of the disease in terms of magnitude, distribution, pace and specificity?

  • It should be global in scale.
  • It should have an influence and presence commensurate with both the scale and pace of the spread of CVD on a worldwide basis, in particular accounting for the rapid rise of the disease in the developing world during the last 40 years.
  • While being appropriately global in scale, it should also be elusive, diffuse, difficult to capture, quantify and correlate in any localised manner, and with high regional variability – the struggle in pinning down the causes of CVD need to be adequately reflected in the actual nature of the underlying cause.
  • It should be a predominantly environmental factor, reflecting the changing risk profiles seen in migrants from low-risk countries to high-risk countries.
  • It should be largely man-made, suiting CVD’s status as a disease of civilisation.
  • It should exhibit a strong affinity for the cardiovascular system, and be shown to be capable, by some clear mechanism, of producing the precise symptoms indicative of CVD.
  • It should consequently have an implicit and identifiable role in each of the major risk factors.
  • It should offer a plausible explanation for those cases of CVD in which an aggregate of the major risk factors aren’t a very satisfactory fit.
  • It should already be staring us in the face.

Surprisingly perhaps – or perhaps not – there is an obvious candidate which appears to fulfil all these criteria. NO! Principally, nitrogen (chemical symbol N) and oxygen (chemical symbol O). More specifically, nitrogen and oxygen conjoined in their various ways: in nitrates (NO3-), nitrites (NO2-) and as various oxides of nitrogen (N2O5, NO2, N2O, NO). (And possibly also involving other nitrogen compounds such as ammonia (NH3).) But, fundamentally and finally, Nitrogen Overload.

How can this be? These compounds have been studied extensively. If they were capable of causing circulatory diseases on the scale we are now experiencing, surely this would have come to light? The major health concerns around their increased presence in the environment focus more on potential carcinogenicity than on anything to do with heart disease. It seems highly implausible, to say the least.

And yet …

Global consumption of nitrogenous fertilisers has increased from around 11.5 million metric tonnes in 1961 to over 84.5 million metric tonnes in 2002. By far the greatest increase has been seen in the developing world with consumption rising from just over 2 million metric tonnes in 1961 to over 56 million metric tonnes in 2002, a 28-fold increase resulting in present consumption rates nearly double that of the developed world. Consumption in the developed world reached a plateau of just under 40 million metric tonnes per annum in the mid 1980s and has subsequently declined by 25%. (Source: FAOSTAT) On top of this, the number of livestock worldwide has more than doubled since 1960 and animal wastes are also responsible for a high level of nitrate pollution.

CVD mortality and World nitrogenous fertiliser consumption

So here is a factor of potentially appropriate magnitude whose usage trends in both the developed and developing world appear to parallel the opposing trends in CVD mortality in each area over the same timescale. (There is a paucity of reliable data for the incidence of CVD in the developing world. Data above is taken from WHO estimates.)

Despite the longer history of fertiliser use in developed countries, which has conceivably resulted in a level of adaptation and habituation to higher environmental nitrogen levels, correlations between nitrate fertiliser use and disease patterns are still evident.

In Denmark, for instance, CVD mortality rates show a noticeable downward trend from 1990 onwards, which correlates with a consistent decline in nitrate fertiliser use starting the year before.

Danish CVD statistics

Elsewhere in western Europe, change in nitrate fertiler use has not generally been so dramatic, so it's less easy to spot clear correlations, although there's little in the data to contradict the hypothesis. At individual country level, the data frustrates simple explanations. The picture is complex and other factors clearly need to be taken into account, not least geography and geology, both determining the propensity of countries' ecosystems to retain high concentrations of nitrates and pass those on to the populations supported by them.

There are strong correlations evident where the right conditions come together, as was the case in Poland following the breakup of the USSR.

Polish CVD statistics

The subsequent decline in ischaemic heart disease was the subject of a study (Zatonski, Witold A, McMichael, Anthony J and Powles, John W. 1998. Ecological study of reasons for sharp decline in mortality from ischaemic heart disease in Poland since 1991 BMJ 1998;316;1047-1051) which, while highlighting the reduction in animal fat consumption (which had already been trending downwards for a decade as CVD mortality still rose) and citing it as a major potential factor, failed to identify any factors which satisfactorily accounted for the sudden and dramatic reversal in CVD mortality rates since 1991. The halving of the country's use of nitrate fertilisers the year before was not considered.

Yet an almost identical set of circumstances in Bulgaria over the same time period appears to have had no effect on the rising CVD mortality figures.

Bulgarian CVD statistics

However, Poland is largely self-contained geographically while much of both Bulgaria and Romania (which shows a similar picture in its statistics), form the lower part of the Danube river basin, both countries consequently receiving extra nitrate input in the form of run-off from countries further upstream. Both countries have massive problems with nitrate pollution of drinking water supplies, the levels being sufficient to contribute to other overt pathology already well correlated with nitrate pollution. (eg. Vladeva S, Gatseva P, Gopina G. 2000. Comparative analysis of results from studies of goitre in children from Bulgarian villages with nitrate pollution of drinking water in 1995 and 1998 Cent Eur J Public Health. 2000 Aug;8(3):179-81) In this context it seems plausible to suggest that reduction in nitrate fertiliser use has so far had little impact on nitrate levels being consumed by the populations of these countries. Bulgaria also tops the European rankings for per capita cigarette consumption.

Clearly the solution is not obvious at the level of detail defined by political boundaries. But we know that already, or we would have found it. If, as is being suggested here, it's the total level of nitrogen overload that needs to be taken into consideration, then this will have various origins with differing degrees of significance from culture to culture, location to location, indeed from individual to individual. The difficulty of pinning down an obvious single factor amongst all the detailed data doesn’t necessarily mean that we should lose sight of the strength of the correlation apparent at the global level. In the context of the progressive globalisation of the food supply and the irrelevance of political boundaries to nitrate contamination of ground and surface water, individual country data is possibly an inappropriate categorisation in any case (although it's all we have to work with in any meaningful way). As the 1999 publication from the World Resources Institute Critical Consumption Trends and Implications: Degrading Earth’s Ecosystems by Emily Matthews and Allen Hammond states, “Great uncertainties are involved in measuring the global distribution and transport of nitrogen, how much is being stored, and where, because reactive nitrogen in its many forms is highly mobile, moving easily between terrestrial, freshwater and marine ecosystems, and the atmosphere.”

A comment from the introduction to this report seems especially pertinent. It points out “What emerges from this analysis is that fundamental changes are taking place in global biological processes. Our attention has perhaps been focused too much at the local and regional level – on specific polluting emissions, or loss of specific habitats and species – and too little on whole ecosystems. Our understanding of how complex ecosystems function remains relatively limited, but the evidence of serious disruption is now widespread. Chronic, human-induced imbalances in major biological systems – for example, nutrient cycling, inter-species relationships and food chains – are more insidious than acute incidents of pollution or other damage. Their consequences, however, may be much harder to reverse, and more serious for the developmental and security prospects of every country.”

Once again it’s this matter of appropriate scale. Of standing back far enough from the problem to be able to focus on a level of detail at which global patterns and correlations are more readily apparent.

Matthews and Hammond go on to say “World cereal consumption has more than doubled in the last 30 years, while meat consumption has tripled since 1961 and is increasing at a linear rate. The agricultural success story is that rising demand has been met; more people are now better fed than they were a generation ago. One of the many environmental consequences, only now becoming clear, is significant disruption of the global nitrogen cycle. In the past half century, the application of inorganic nitrogen fertilizers world-wide has increased more than ninefold, and the number of livestock has more than doubled since 1960. Fertilizers and animal manures have increased and concentrated, respectively, the amount of nitrogen entering soils, freshwater and marine ecosystems. Human activity has actually doubled the natural annual rate of nitrogen fixation, and by far the largest single cause is agriculture.

This seems a hugely significant set of facts. It has the feel of an appropriate order about it, an appropriate scale, an appropriate proportion, befitting a disease that accounts for more than 30% of all deaths worldwide. It also demonstrates an appropriate quality of elusiveness; difficulties in measurement, quantification and consistent follow-through at more localised levels.

Yet these factors alone are nowhere near sufficient to impute a causative role. There needs to be a firm and direct causal connection. If this can’t be found readily with any hard and fast consistency in all the myriad risk factors identified amongst various collective groupings of CVD cases, then perhaps it can be found at a different level of detail: at the level of the specific impact of nitrates on the cardiovascular system.

Victims of paradox?

Is there a demonstrable affinity between nitrogen compounds and the cardiovascular system? Indeed there is. A strong one and an appropriately specific one. Nitrates have been used extensively and successfully for over 100 years in the treatment of cardiovascular disease, both in acute emergency treatment of heart attack and angina, and in longer term treatment of angina and left ventricular dysfunction. Well then surely that’s a contradiction? If nitrates are used to successfully treat CVD, then how on earth can they be the cause of it? Increases of nitrates in the environment would, if anything, be expected to be beneficial.

Not necessarily. The impact of any substance on the human organism is dose-dependent. Recent studies in toxicology, particularly in the area of ionising radiation research, have confirmed and repeatedly replicated evidence of the existence of a paradoxical twist in the dose-response curve. This effect, known as hormesis, is a revival of a 120 year-old observation known as the Arndt-Schulz law which stated that low doses of a substance have a stimulatory effect in contrast to the inhibitory impact of medium to high doses. Since modern pharmacology works almost exclusively in the inhibitory range of the dose-response curve, the Arndt-Schulz law all but disappeared from modern texts. The term hormesis was coined by C Southam and J Erlish in the early 1940s following their discovery that low doses of oak bark extract, normally inhibitory to fungal growth, paradoxically stimulated it.

Hormesis has been slow to catch on and has met with some resistance; it does, after all, seem slightly counter-intuitive. However, studies have continued. Challenging mice with small doses of gamma ray radiation shortly before irradiating them with very high levels of gamma rays was found to decrease the likelihood of them going on to develop cancer (Bhattarcharjee D, 1996. Role of radioadaptation on radiation-induced thymic lymphoma in mice. Mutation Research, 358, 231-235). There is a similar effect when dioxin is given to rats.

The hormesis model appears to have wide application and substantial evidence for it is mounting. Workers at nuclear power plants in both the UK and Canada who are subject to continual low background radiation have been shown to have a lower incidence and mortality from cancer: in the Canadian case, 58% below the national average (Abbat., J D, Hamilton, T R and Weeks, J L, 1983. Epidemiological studies in three corporations covering the Canadian nuclear fuel cycle; Biological effects of low level radiation, IAEA, Vienna, 351). Common instances of hormesis are not hard to find. Substances such as alcohol and caffeine have mild stimulating effects in low doses but are inhibitory or even lethal in high doses. There’s even evidence to suggest that alcohol in low doses may diminish the risk of developing CVD while higher doses are associated with greater morbidity and mortality.

Dose-response curve according to the Arndt-Schulz law and Hormesis

Habitual exploitation of the hormetic effect can produce quite dramatic results. Gustav Schenk, in his 1955 ‘The Book of Poisons’ recounts “I have seen and spoken to many arsenic eaters in Styria, Lower Austria and Carinthia. Woodcutters, hunters and mountain guides in these districts believe that arsenic makes the breathing easier and the step more certain. I myself saw a porter in Deutsche-Landsberg at the foot of the Kor Alp consume a lump of arsenic the size of a pea. I estimated it at almost half a gramme.” This is four times the usual fatal dose.

While the most prominent studies of hormesis involve low doses of toxins producing paradoxically beneficial effects, this is not part of the definition of hormesis. The key is that low doses show the opposite effect of high doses. If nitrates demonstrate hormesis, then it is entirely possible that these substances which show such a specific inhibitory action on the symptoms of cardiovascular conditions at moderate doses are capable of stimulating those same symptoms at much lower doses. The vasodilatory effect produced by nitrates at moderate to high doses would become a vaso-occlusive stimulus at low doses. Blood pressure lowering becomes blood pressure raising.

Possible. Yet how does it account for the fact that mortality statistics in developed countries started to decline while consumption of nitrogenous fertilisers and animal waste pollution were still rising? Two possible lines of reasoning come to mind.

Firstly, it’s possible that habituation to long-term low dosage levels in developed countries may explain the lesser degree of reactivity when compared to developing countries, much as the Styrian arsenic-eaters were able to tolerate doses well in excess of lethal levels. The extensive use of fertilisers in agriculture began in earnest around the 1830s with the commercial exploitation of Chilean guano deposits. At the turn of the 19th century, heart disease was the fourth leading cause of death in the US, behind pneumonia/influenza, tuberculosis, and diarrhoea/enteritis/intestinal ulceration. Artificial fertilisers were first produced in 1905 and commercial production began soon after. CHD mortality statistics showed a sharp upward trend around 1920, and by 1940, heart disease and cancer had achieved the highest death rates in the country. Mortality rates for heart disease peaked in 1963 and have declined steadily since (Howell, J. ‘Concepts of Heart-Related Diseases’. The Cambridge World History of Human Disease, 1993).

Europe was generally slower to adopt the widespread use of artificial fertilisers, with much of the growth in their use occuring post WWII. CVD mortality trends also peaked later than in the US, generally occurring 10-15 years later with the first real sustainable declines not evident until the 1980s.

Yet there are exceptions to the general downward trend in CVD mortality in the developed world. Mortality rates in Scotland, for instance, remain among the highest in Europe. Gastro-oesophageal cancer, the development of which has been linked to nitrate levels, is also exceptionally prevalent in Scotland and is the fastest growing cancer in the UK. This leads to the second possibility. Which is that the supplanting of CVD at the top of the mortality statistical rankings by malignancy is also linked to environmental nitrogen levels (see below).

Of course much work remains to be done to establish possible correlations at regional and local levels, and to account for all the various anomalies present in the data, as well as to fully investigate the impact of low nitrate doses on cardiovascular health. It’s not the purpose of this article to attempt an explanation of every apparent exception to the overall pattern. Its aim is rather to focus on the pattern as a whole: the overall congruence in magnitude, distribution, pace and specificity between cardiovascular disease and environmental nitrate pollution and to suggest that the apparent correlation is worthy of an extensive and comprehensive research programme.

So far then we have a factor of an appropriate global magnitude and extent, which is frustratingly difficult to measure and quantify in any localised manner, and which has an appropriate focus on the cardiovascular system with a plausible mechanism for its action.

Risky business

The next question is whether or not the role of nitrogen compounds is evident and significant in each of the major risk factors for CVD so far identified.

Tobacco. Cigarette tobacco contains variable but significant quantities of nitrates, depending on the source of the tobacco and the method of curing. Nitrates decompose into nitric oxide (NO) on burning and nitric oxide is a notable constituent of the gas phase of tobacco smoke. Since the 1960s, the American tobacco industry has embarked on a programme to reduce the carcinogenic effects of cigarette smoke and this has been achieved in part by using blends rich in nitrate which appear to inhibit the formation of carcinogenic compounds ( UK Scientific Committee on Tobacco and Health Technical Advisory Group: Review of Emissions in Cigarette Smoke, 1998).

Poor diet. A diet that is low in fibre, fresh fruit and vegetables and high in salt, nitrates, fat, animal protein and starch has been identified as a major risk factor in the development of CVD. (Such a diet has also been identified as having a strong association with the incidence of stomach cancer, particularly in developing countries.) Nitrates and nitrites are used extensively in the food processing industry in the preparation of meat products to preserve colour and prevent the growth of botulinum bacteria. They are also present naturally in fresh fruit and vegetables, prompting the authors of the Scottish study on the association of nitrates with gastro-oesophageal cancer to call into question the health benefits of these foods. However, studies appear to show that nitrates from vegetables cycle through the body in about 18 hours. Animal protein, the synthesis of which is a major part of the metabolic nitrogen cycle, metabolises much more slowly. Perhaps this factor, together with the amounts of nitrogen contained in protein (not to mention the nitrites used in its preservation), is what gives higher levels of consumption of these foods a higher statistical correlation with CVD.

It's important to realise it's not a case of nitrates = good or nitrates = bad. Nitrates have a vital role in many metabolic processes and are even produced by microbes naturally in the gut. What is crucial is maintaining the right balance. Neither negative nor positive, but in balance, much as the same balance is crucial in the global nitrogen cycle.

Sedentary lifestyle vs. exercise. The majority of studies in the toxicity of nitrates and nitrites have concentrated on the impact of high doses which can produce a condition called methaemoglobinaemia – an impairment of the ability to deliver oxygen to the body through the blood. However, an Environmental Health Criteria report published jointly by the United Nations Environment Programme and the World Health Organisation in 1978 on Nitrates, Nitrites and N-Nitroso Compounds highlighted the following piece of research. “In an effort to develop sensitive tests for the detection of the possible effects of subclinical methaemoglobinaemia, behavioural studies with mice were undertaken by Behroozi et al., 1971. Groups of … mice were given nitrites in their drinking water at doses … considered to be in the subclinical range. The results showed a significant reduction of overall motor activity in the groups receiving the highest levels of nitrites.” Could this research provide the basis for suggesting that the increasing tendency towards a sedentary lifestyle seen throughout the industrialised nations in recent decades and now spreading to the developing world may well be a function of continual low subclinical doses of nitrates and nitrites?

As for the beneficial impact of exercise, recent research has focused on the role of nitric oxide (NO) in the regulation of muscle contraction and metabolism. “Recent human data indicate that NO plays a role in muscle glucose uptake during exercise ... Exercise training in healthy individuals elevates NO bioavailability through a variety of mechanisms ... Such adaptations likely contribute to increased exercise capacity and cardiovascular protection ... Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training conveys benefit in the setting of secondary prevention.” (Kingwell, B A, 2000. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. The FASEB Journal. 2000;14:1685-1696) Research conducted in Poland in 1991 also indicated that exercise increased the toxicity of nitrates and nitrites fed to laboratory rats (Grudzinski I, Szymanski A, Chomiczewski K. The effect of exercise associated with subchronic poisoning with potassium nitrate and sodium nitrite on the processes of intestinal absorption of D-xylose in rats. Arch Environ Contam Toxicol. 1991 Sep;21(3):462-7).

If this is the case, then it would seem plausible to suggest that exercise increases the bio-availability of a range of nitrogen compounds, temporarily elevating the effective dose and increasing the throughput of nitrogen. In individuals already suffering from the symptoms of CVD (higher end of stimulatory dose range), this may be sufficient to elevate the effective dose into the inhibitory phase of the dose-response curve, accounting for the immediate relief of symptoms that some individuals experience with exercise. In asymptomatic individuals (lower end of stimulatory dose range), a sudden increase in available nitrogen resulting from unaccustomed vigorous exercise may be sufficient to elevate the effective dose into the range in which it can precipitate symptoms (potentially accounting for the number of heart attacks that occur apparently "out of the blue" as a consequence of abnormal and vigorous exercise). This hypothesis would also support the findings that gradual build-up to a programme of regular exercise has significant benefits, since temporary dose elevations would stay within tolerance ranges and the emphasis would consequently be on increasing nitrogen throughput.

Obesity. Recent studies have demonstrated a strong correlation between nitric oxide concentrations and body fat (Jong Weon Choi, Soo Hwan Pai, Soon Ki Kim, Masafumi Ito, Chang Shin Park and Young Nam Cha. 2001. Increases in Nitric Oxide Concentrations Correlate Strongly with Body Fat in Obese Humans. Clinical Chemistry. 2001;47:1106-1109) while other studies have suggested a role for NO in the regulation of food intake in animal experiments. Again it seems that we’re looking at a situation of nitrogen overload.

Urban/industrial environments. The nitrogen content of industrial wastes is highly variable, but industries identified as significant contributors of nitrogen pollution are petroleum refineries and the fuel and food processing industries. Both petrol and diesel engines emit oxides of nitrogen through fixation of atmospheric oxygen and nitrogen in the combustion chambers of the engine at high temperature and pressure. Nitric oxide and nitrogen dioxide predominate. Power generation from the burning of fossil fuels is another significant contributor of NO to the atmosphere.

Diabetes. In 1997 a study by the University of Leeds Paediatric Epidemiology Group found clear links between increased levels of nitrate in water and the incidence of diabetes in children. The summary of the study notes “The Yorkshire-wide study, the first ever to examine the issue in detail, identified much higher levels of childhood diabetes in rural areas – up to 25 percent greater – where nitrate levels in water were up to four times higher than in urban locations. The most badly-hit areas are in East Riding and rural areas of North Yorkshire. The average nitrate level in drinking water in East Riding was 30 milligrams per litre, compared to 7 milligrams per litre in urban areas of West Yorkshire. The recommended EC limit is 50 milligrams per litre. Increased nitrate levels are largely caused by agricultural run-off from fertilisers. The study analysed data supplied by Yorkshire Water plc – but all samples surveyed were below the recommended EC limits. More than 2,000 Yorkshire children have been newly-diagnosed with diabetes since a specialist register was set up in 1978. Environmental factors are major determinants in causing diabetes in children as fewer than one in ten young diabetics have a relative with the illness. The majority of adults who suffer from diabetes are non-insulin dependent; for children, diabetes is a chronic autoimmune disease requiring a lifetime of daily insulin injections. Nitrates and their chemical breakdown products, nitrosamines, are known to cause diabetes in animals and have been linked to cancer, thyroid problems and birth defects. Infants and young children are believed to be particularly vulnerable to nitrate exposure.”

So now in addition to being a factor of an appropriate global magnitude and extent, which is frustratingly difficult to measure and quantify in any localised manner, and which has an appropriate focus on the cardiovascular system with a plausible mechanism for its action, we now have a potential identifiable role for nitrates in each of the major risk factors for CVD.

To recapitulate and summarise, what I am suggesting here is that the underlying cause of CVD is nitrogen overload. The dosage required to produce the symptoms of the disease is in the stimulatory phase of the dose-response curve. The dose comprises two principal components: a "global" element and a "specific" element. The global element provides the base dose; a constant (though locally variable) and growing proportion of the overall dose which, although itself not high enough to produce overt symptoms in the majority of the population (except perhaps that 20% that aren't accounted for by the established risk factors), is nevertheless an essential component of the overall dose. The specific element – arising through additional nitrogen input via any combination of the established risk factors – raises the base dose to the level required to produce symptoms, though the total dose remains within the subclinical range. As dosage levels increase, so the symptom picture evolves, eg. obesity and sedentary habits would appear to be a consequence of dosage levels towards the upper end of the subclinical range, possibly also diabetes, and the comparatively recent appearance of these symptoms on a widespread basis would appear to suggest that the global element of the dose may still be rising.

This scenario appears consistent with what we have observed in the aetiology of the disease and is also consistent with the evolving patterns of incidence. Essentially it would appear that addressing the specific element of the dose delays, but cannot prevent, the onset of the disease, so it would seem plausible to suggest that the general slowing of metabolism that occurs in old age may increase sensitivity to the global element of the dose.

But it gets worse. The implications hinted at in the examination of the role of nitrates and nitrites in the various established risk factors for CVD are that nitrogen overload may be responsible for far more than just the epidemic of CVD, as if that in itself weren’t enough. Malignancy, the new term given to that most emotive of words, cancer, is the second major cause of death throughout much of the world. It too has exploded onto the global death charts in the latter half of the 20th century. A steadily growing number of studies are linking nitrosamines, the breakdown products of nitrates and nitrites, with the development of various cancers. Then there are all the other modern "syndromes" which have appeared in the last 50 years which the latest research is also linking to NO excess – conditions such as Chronic Fatigue Syndrome, Fibromyalgia, Multiple Sclerosis, Alzheimer's Disease, Parkinson's Disease and other inflammation-mediated neurodegenerative conditions, Multiple Chemical Sensivity, even Post-traumatic Stress Disorder. Research has also identified a role for NO in immune and inflammatory responses. Could the recent appearance of a variety of auto-immune conditions and inappropriate inflammatory responses (allergies) to a wide range of harmless substances be connected to nitrogen overload as well? It seems plausible.

The picture emerging is an enormously disturbing one, but one that nevertheless makes sense of all the changes we've seen in our health over the last 50 years, and the apparent powerlessness of medical science to do much about it. Human interference in the global nitrogen cycle has resulted in a positive bias to the cycle by a factor of 2. In other words, we are putting into material form twice the amount of nitrogen than is able to cycle back into gaseous form in the atmosphere, massively disrupting the global balance. This imbalance on a global scale is being echoed in each and every one of us, in our own individual metabolic nitrogen cycles, as our bodies struggle to keep the optimum balance between what we ingest and what we excrete. As we become progressively stressed by the continual positive bias in input, the effect of the overload suppresses natural reactions to restore balance – such as exercise. But of course, exercising increases the amount of nitrogen we excrete back into the environment. It’s a vicious circle.

The evidence is fairly stacking up. How much more do we need? There is so much research now it really seems just a case of joining the dots. That, after all, is pretty much all I’ve done here. The longer action is delayed, the more intransigent the situation becomes, the more lives are lost, the more the economic cost of supporting a chronically sick global population increases, the more we stress the global ecosystem. Yet attempts at national and international level to limit the use of nitrogenous fertilisers, both artificial and in the form of animal wastes, have met with resistance from agribusiness and the agricultural community. More stringent controls have been conceded in many instances through intense lobbying and demands for more concrete proof. People’s livelihoods are at stake in an industry already hard-pressed for economic survival. Understandable, of course, but ultimately parochial and short-sighted.

The burden of cardiovascular disease, and other conditions becoming ever more clearly associated with nitrogen overload, are problems of global proportions: and problems of global proportions require global solutions. We are open systems – we breathe, we eat, we excrete – and we cannot insulate ourselves from the effects of a massive imbalance that is all around us. No amount of health measures will solve the problem. We are simply brushing the snow from the door. How much longer can we put off drastic and concerted action on the basis that we lack sufficient concrete evidence of something which we could spend the next century trying to pin down sufficiently well to satisfy the sceptics? What price our profligate lifestyle if as much as half of the world’s annual mortality is a direct result of it? If we are stressing the global ecosystem to a point beyond its capacity to recover? It is totally unacceptable. Words like “heartlessness” spring to mind rather too readily, and it’s tempting to suggest that this in itself may represent the real heart of the matter. Purely economic interests have dominated the world stage for far too long. It’s time for a change of heart.

Further Reading:

There are a large number of internet resources explaining the Nitrogen cycle, both in global terms and within our own metabolic processes. These are some.

Global Nitrogen Cycle (1)
Global Nitrogen Cycle (2)
Metabolic and Global Nitrogen Cycles (basic)
Metabolic Nitrogen Cycle (advanced)


© Wendy Howard, June 2005. Additional data added January 2007.
General Essays | Time for a Change of Heart?
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