Cardiovascular Disease Susceptibility and Resistance in Circumpolar Inuit Populations

Accepted Manuscript Cardiovascular disease susceptibility and resistance in circumpolar Inuit populations Maria Tvermosegaard, MD., Inger K. Dahl-Petersen, M.Sc. PhD., Nina Odgaard Nielsen, M.Sc. PhD., Peter Bjerregaard, MD. Dr.M.Sc., Marit Eika Jørgensen, MD. PhD. PII:

S0828-282X(15)00426-2

DOI:

10.1016/j.cjca.2015.06.002

Reference:

CJCA 1704

To appear in:

Canadian Journal of Cardiology

Received Date: 16 March 2015 Revised Date:

5 June 2015

Accepted Date: 5 June 2015

Please cite this article as: Tvermosegaard M, Dahl-Petersen IK, Nielsen NO, Bjerregaard P, Jørgensen ME, Cardiovascular disease susceptibility and resistance in circumpolar Inuit populations, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.06.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Cardiovascular disease susceptibility and resistance in circumpolar Inuit populations Maria Tvermosegaard, MD.1,2, Inger K Dahl-Petersen, M.Sc. PhD.1, Nina Odgaard Nielsen, M.Sc.

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PhD.1, Peter Bjerregaard, MD. Dr.M.Sc.1,3, Marit Eika Jørgensen, MD.PhD.1,2

National Institute of Public Health, University of Southern Denmark

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Steno Diabetes Center, Gentofte, Denmark

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Greenland Centre for Health Research, University of Greenland.

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Short title: CVD risk among Arctic Inuit

Word count: 6044

Corresponding author:

Steno Diabetes Center Niels Steensens vej 2 2820 Gentofte, Denmark

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Marit Eika Jørgensen,

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tlf: +45 30756008, E-mail: [email protected]

ACCEPTED MANUSCRIPT Abstract Cardiovascular diseases (CVD) are major public health issues in indigenous populations in the Arctic. These diseases have emerged concomitantly with profound social changes during the last 60 years. The aim was to summarise the literature on CVD risk among Arctic Inuit. Literature on prevalence, incidence and time trends in CVD and its risk factors in Arctic Inuit populations was

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reviewed. Most evidence support a similar incidence of coronary heart disease and a higher

incidence of cerebrovascular disease among Arctic Inuit compared to western populations. Factors that may increase CVD risk include ageing of the populations, genetic susceptibility, a rapid increase in obesity, diabetes and hypertension parallel with decreasing physical activity and

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deterioration of the lipid profile. Contrary, and of great importance, there has been a decrease in smoking and alcohol intake, at least documented in Greenland, and contaminant levels are

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declining. Although there have been marked socio-economic and dietary changes, it remains unsolved and to some extent controversial how this may have influenced cardiovascular risk among Arctic Inuit. The increase in life expectancy in combination with improved prognosis for patients with manifest CVD will inevitably lead to a large increase in absolute numbers of people affected by CVD in Arctic Inuit populations, exacerbated by the rise in most CVD risk factors over the last decades. For preventive purposes and for health care planning it is crucial to carefully monitor

Summary

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disease incidence and trends in risk factors in these vulnerable Arctic populations.

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The social transition among Arctic Inuit and its association with CVD risk is complex. Factors that may increase CVD risk include improved life expectancy, genetic susceptibility, a rapid increase in

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obesity, diabetes and hypertension parallel with a decrease in physical activity and deterioration of the lipid profile. Contrary, there has been a decrease in smoking and alcohol intake. It remains unsolved how socio-economic and dietary changes may have influenced cardiovascular risk among Inuit.

Introduction

Metabolic and cardiovascular diseases are major public health issues in the 21st century among indigenous populations in the Arctic. These diseases have emerged concomitantly with and possibly as a consequence of the profound social changes during the last 60 years although the causal mechanisms are not sufficiently established. Western populations have experienced a rapid decline in CVD over the past decades, but it remains unknown whether a similar trend has occurred among

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ACCEPTED MANUSCRIPT circumpolar populations. Life expectancy in circumpolar populations is rising sharply and people are exposed to cardiovascular risk factors such as tobacco use, physical inactivity, unhealthy diet, obesity and diabetes for longer periods. However, contrary to what has been observed in developing countries, urbanisation itself is not associated with increased cardiovascular risk in some circumpolar populations. While information about CVD among Arctic indigenous populations is

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limited, the circumpolar Inuit are indigenous populations for which both information about the social transition and the disease pattern is exceptionally good. Arctic Inuit populations include Greenland and Canadian Inuit, Alaska's Yupik and Iñupiat, and Siberian Yupik1(figure 1). Our aim is to summarise the literature on prevalence, incidence and time trends in cardiovascular risk among

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Inuit populations in the Arctic region.

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Time trends in socio-demography

The Inuit in Greenland, Northern Canada and Alaska have during the second half of the 20th century undergone profound demographic and socioeconomic changes while their homelands have partly transited from small hunting communities to modern towns of several thousand inhabitants. What used to be inaccessible or even forbidden areas the arctic regions are now totally integrated in the global political and economic systems. In Greenland, the indigenous population has more than

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doubled since 1950 and the proportion of southern immigrants has increased from 4% to 11% with a peak of almost 20% in the 1970s and 80s. About one third of the Inuit population is under the age of 15 compared with less than 20% in Canada as a whole. The traditional hunting economy has overall been replaced by wage earning and social welfare. While the indigenous peoples are on

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average less well off than their fellow citizens nationally, marked economic disparities also exist

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within Inuit communities. Life expectancy is low1.

Cardiovascular disease burden among Inuit populations Early studies from Greenland indicated that coronary heart disease was infrequent2 and since the 1970s it has been a common notion that CVD in general is rare among Inuit populations. Although the evidence was fragmented, this perception attained status as the invariable truth in the atherosclerosis literature3 put forward in the mid-1970s ‘coronary atherosclerosis is almost unknown among these people [the Greenland Eskimos] when living in their own cultural environment’4. This statement was followed by the suggestion that a high intake of polyunsaturated fatty acids (PUFAs) through the traditional marine diet protected against coronary heart disease

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ACCEPTED MANUSCRIPT (CHD)5. The claim that coronary atherosclerosis was rare opposed the classic 1940 description of the disease and mortality pattern among the Inuit of Greenland by Alfred Bertelsen6. Based on systematic reports of medical officers since 1838, Bertelsen stated ‘arteriosclerosis and degeneration of the myocardium are quite common conditions among the Inuit, in particular considering the low mean age of the population’. Furthermore, the hypothesis of an association

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between high intake of PUFAs and low occurrence of CHD was not based on systematic studies7, 8. A review from 2003 based on literature and up-dated analyses of the mortality statistics found that mortality from all CVD combined is higher among the Inuit than in white comparison populations8. It showed that mortality from ischemic heart disease has decreased while mortality from

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cerebrovascular disease has remained at a steady high rate. More recently, registry data from the Indian Health Service in Alaska from 2009 showed that CVD mortality is higher among indigenous

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Alaskans (including both Alaska Inuit and Indians) 9. Furthermore, there was a decline in CVD mortality in Whites after 1990, but less so among indigenous Alaskans10. Since mortality statistics may reflect diagnostic practice and quality of treatment rather than the incidence of CVD, a population-based study was performed in Greenland with the aim of providing a better estimate of the prevalence. This study focused on markers of coronary heart disease from 1999-2001, and showed an overall coronary heart disease prevalence of 10 % and ischemic ECG changes in 13 %,

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which is not different from that in western populations11. Another study of among Inuit in Nunavik from 2009 showed an equally high degree of atherosclerosis assessed by ultrasound of intima-media thickness12. Registry-based studies from 2003-2012 have also shown similar incidence rates for populations13, 14.

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coronary heart disease while cerebrovascular events are more frequent than in western comparison

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Changing Prevalence of Risk Factors among Inuit populations Understanding of early determinants of CVD is essential for disease prediction and prevention strategies. Social position is a determinant of health and health behaviour among the Inuit as in Western populations. There are no studies of cardiovascular end points according to social position among the Inuit, but especially from Greenland studies have documented associations between on the one hand social position and on the other hand smoking, diet, obesity and physical activity. The current section summarises information on the most established behavioural, biological, and environmental factors of CVD among circumpolar Inuit. Other factors of potential importance in these populations include fetal and early life factors, mental stress and early treatment and detection of disease. Systematic information on these risk factors is however not available.

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Behavioural risk factors Smoking: As in other developing societies smoking is disproportionately prevalent among Arctic Inuit (table 1), not only among adults but also among pregnant women and adolescents15-26. However, cigarette

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import has decreased1, and unpublished results from recent population surveys in Greenland show a decrease in smoking prevalence. Reported prevalence rates of smoking were roughly twice as high among indigenous Alaskans and Arctic Canadian Inuit compared with non-natives15, 26 and among Inuit in Greenland compared with Danes23. Smoking is a well-known risk factor for CVD, but

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epidemiological studies linking smoking and CVD among Arctic indigenous people have to our

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knowledge not been published.

Physical activity:

Modernization has resulted in a less physically challenging daily life where sedentary occupations have become more prevalent1. However, many of the traditional subsistence activities have become a part of the modern Arctic society as leisure time pursuits1. In a population-based cohort of Alaska Inuit, physical activity (PA) was found to be inversely associated with prevalent CVD27 and to have

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beneficial effects on lipid levels and blood pressure28.

The impact of the social transition on physical fitness levels has only been exemplified in one prospective study; a 20-year study in an Inuit community in the Northwest Territories, which

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showed a temporally decrease in fitness level29,30. More recently, a population-based study among Inuit in Greenland found higher PA levels among those with a more traditional lifestyle (hunters

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and fishers) compared to those with a more modern lifestyle31. Findings from a cohort study of Inuit in Nunavik revealed that a sedentary lifestyle was reported by 55% of individuals 16. In a cohort study of indigenous Alaskans, 23% of participants reported less than 30 minutes per week of moderate or vigorous activities28. Women are found to be less active than men32,33, and living in rural areas, higher socioeconomic status, traditional food use and participation in cultural activities are factors positively related to PA among American Indians and indigenous Alaskans28,34.

Alcohol:

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ACCEPTED MANUSCRIPT Misuse of alcohol is a major public health problem among Inuit populations and a determinant of poor health and social problems. The level of alcohol consumption among Inuit populations has changed over the last 50 years and has included regional restrictions in availability of alcohol. In Greenland the consumption increased from low levels in the 1950s to very high levels in the 1980s. Since then, consumption has declined to an average yearly consumption equivalent to 8.8l of pure

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alcohol per person aged 15 and above1,35. In Nunavik, a 17% increase in alcohol was reported from 1992 to 2004. Although the drinking prevalence in Inuit communities was lower compared to the rest of Canada, 24% of the current drinkers reported a high alcohol consumption at the same occasion at least once a week, which was three times higher than elsewhere in Canada36. While

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modest alcohol intake is associated with lower stroke incidence and mortality, the risk increases substantially with heavier drinking. Inuit populations have shown common traits in drinking

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patterns with a high prevalence of binge drinking 35-37. Studies on alcohol consumption and CVD risk among Inuit are sparse. Early studies of the lipid profile among Inuit in Greenland showed that alcohol consumption was associated with lower levels of VLDL+LDL cholesterol38 and higher HDL cholesterol30.

Diet

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The diet of the Inuit has become increasingly westernized during the last century. In Greenland, traditional food of mostly marine origin accounted for 82% of the energy intake around 190039, 35% in 195440 and has during the last 60 years been slowly but steadily decreasing to 21%41 . In the 1960s the Inuit in Greenland were flashed as a population with a very high intake of long chain

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polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and a very low cardiovascular mortality. The Inuit link has not survived a closer scrutiny6-7 and

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numerous observational and interventional studies of the effects of DHA and EPA have failed to give convincing evidence of their power to reduce the incidence of CVD at the population level42,43. The challenge of contemporary diet among the Inuit is not so much the decrease in traditional or marine food items but their replacement by imported food of low quality such as food items rich in saturated fatty acids, junk food, sweets and soda pop. In addition, the imbalance between energy consumption and energy expenditure has resulted in a population which is steadily becoming more and more obese. In brief, the discourse of diet and cardiovascular risk is similar among the Inuit and in western populations, but the expected increase in cardiovascular mortality due to the demonstrated dietary transition is not evident.

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Biological risk factors:

Obesity Several studies of Inuit indicate that this ethnic group has high levels of obesity based on BMI and

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waist circumference according to international guidelines with a crude prevalence ranking from 1525% in the adult population44-47. The prevalence of abdominal and overall obesity has increased over the last decades, and obesity increases with social position, particularly among men. However, the metabolic impact of different levels of obesity, at least cross-sectionally, appears to be less

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pronounced among the Inuit than among Europeans, especially for indicators such as HDL cholesterol, triglycerides and blood pressure44,45. It has been shown that the amount of

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subcutaneous fat for a given level of waist circumference is substantially higher among Inuit compared to most other populations, potentially a result of long-term adaptation to the Arctic cold48. Although subcutaneous fat provides insulation, it is cardiometabolically less active. Thus, the high waist circumference in Inuit populations is to a large extent explained by high amount of subcutaneously stored adipose tissue, and this may contribute to the apparent lower cardiometabolic risk for a given level of obesity compared to western populations. Indeed, a need for higher cut-off related diseases49.

Diabetes

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points for obesity has been suggested despite the increasing threat of diabetes and other obesity-

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Studies of diabetes among Inuit before the 1980s found a very low prevalence of diabetes compared to Western populations50. Later studies suggested an increase in prevalence12,51-54 (table 2), and two

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recent population studies among more than 4000 Greenland Inuit found a notably high prevalence of diabetes (9%) and pre-diabetes (19%) in the adult population55, 56. A much lower prevalence of diabetes of 3% has been found in a combined study of four cohorts of indigenous Alaskans54. The latter is the likely consequence of diagnosing diabetes solely on the basis of fasting glucose, which is known to underestimate the true prevalence markedly. A recent study discovered a genetic variant among Greenland Inuit in TBC1D4 that strongly associates with insulin resistance in skeletal muscle and deterioration of postprandial glucose homeostasis57. This variant increases the risk of diabetes with an Odds Ratio of 10.3 and explains about 10-15% of all diabetes in Greenland.

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ACCEPTED MANUSCRIPT The long isoform of the TBC1D4 variant is expressed also in heart muscle, potentially influencing vascular function and risk of CVD, but this hypothesis warrants further studies.

Blood pressure: Hypertension is an important risk factor for coronary heart disease and stroke58. Studies on blood

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pressure among Inuit have provided inconsistent results, probably due to differences in protocols, age composition of study populations and small sample sizes59. Some studies have found lower blood pressure among Inuit than in the general populations60, 61. Other studies have found similar blood pressure levels62, 63 and higher blood pressure64. A systematic review from 2014 found that

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overall hypertension rates were lower among indigenous populations compared with the white background populations (23,4 % vs. 31,2% respectively) and mean blood pressures were similar

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(123.3/75.1 vs. 124.9/75.2 mmHg respectively)65. An increase in hypertension rates and blood pressures was found up to 1999 and expected, as a similar trend was seen in the general populations with increased westernization66. However, a decrease in the level of hypertension and blood pressures was found among the Inuit in the years after the millennium, whereas the general populations seem to have increasing levels67. In 2003 a study found that a mixed sample of Inuit global scale68.

Lipids

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had lower blood pressure compared with most European populations, but ranked intermediate on a

Inuit have in many studies been found to have a CVD protective lipid profile with higher high

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density lipoprotein cholesterol (HDL) and lower triacylglycerol (TG) than the general populations, due to their traditional marine diet and unique genetic background23, 69-70. A favourable lipid profile

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involves high HDL and low TG, low-density lipoprotein (LDL) and total cholesterol71. Among Arctic Inuit, total cholesterol has been found to be at levels comparable with the general populations and following the same trend increasing with age4, 23, 60, 72. One study indicated that genetic heritage was associated with serum lipids showing higher HDL among participants with three or more Inuit grandparents comparing to participants with one or two Inuit grandparents69. Study results have not been uniform and in two studies, a positive association of a marine diet with HDL was confirmed, but not an association with TG72, 73. Paradoxically, a marine diet has also been associated with elevated total cholesterol and LDL72. One study indicated that serum lipids were significantly associated with urbanisation and migration among the Inuit, the effect being due in part to diet

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ACCEPTED MANUSCRIPT change. The same study also found that urbanisation within Greenlandic Inuit was associated with a more risky lipid profile while migration to Denmark showed a favorable change in lipid levels69.

Genetics: Genetic factors are important to consider in relation to the susceptibility to developing any disease,

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and with the newer cheaper large-scale next generation sequencing methods, genetic research has been revolutionized since its beginning in the 1970s. The Inuit split from the Native Americans when their common ancestors lived in, or around, Beringia more than 15,000 years ago74. The Inuit population is highly genetically differentiated from other populations, such as Europeans or East

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Asian, most likely due to it being isolated and affected by bottlenecks in populations size and generally small population sizes for thousands of years. While more than 80% of the Greenlanders

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have some European ancestry; on average ~25% of their genome, there is no evidence supporting historical admixture between the Inuit and the Norse Vikings75.

A study from 1997 examined the prevalence of five known CVD risk alleles in a Canadian Inuit population where mortality rate from coronary heart disease was lower than the general Canadian population. Inuit had lower TG, LDL and higher HDL than the general population, although results showed a higher prevalence of four out of 5 alleles associating with hypertension, insulin resistance,

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CHD and elevated LDL76. More recently, a study among 3324 Inuit from Greenland, Canada, and Alaska identified a common low-density lipoprotein receptor p.G116S associated with an increase in LDL cholesterol of 0.54 mmol/L per allele, which is >3× larger than the largest effect sizes seen with other common variants in other populations77. In contrast, a study on Yup’ik Inuit found a

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positive association of the P479L (rs80356779) variant with HDL cholesterol despite being associated with all obesity-related traits78. All in all it seems fair to say that the Inuit indeed are a

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genetically distinct group, and genetic studies suggest that Arctic Inuit are susceptible to cardiometabolic disease, although the interaction between risk genes and lifestyle factors is not clarified.

Environmental risk factors The Arctic was formerly considered a pure environment and the Inuit unaffected by environmental contaminants due to their remote residence far from agricultural and industrial regions. However, studies conducted in the mid-1980s and early 1990s identified environmental contaminants, including heavy metals and organochlorines in the Arctic ecosystem79. Organochlorines

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ACCEPTED MANUSCRIPT bioaccumulate in fish and sea mammals, which constitute the majority of the Inuit traditional food. Very high concentrations of a wide range of contaminants have been reported among adult Inuit 7982

. High concentrations of contaminants including PCBs, methylmercury, lead and cadmium have

also been measured in umbilical cord blood83-88 and breast milk83, 84, indicating profound prenatal exposure. Studies from Greenland have also documented high concentrations of several

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contaminants pregnant women89, 90 and newborn children89. Legislation against release of

contaminants from agriculture and industries in southern regions combined with a reduced intake of traditional food as part of the profound lifestyle transition among Inuit populations, has resulted in a marked decrease in contaminant levels measured in Inuit in Greenland (e.g. PCB levels reduced by

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41% from 1993-2009)91 and Arctic Canada (e.g. PCB levels reduced by 7.9% per year from 19942001)88. Only few studies of the influence of contaminants on CVD risk have been conducted

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among Inuit and these have shown conflicting results. Thus, a study among Inuit in Arctic Canada reported an association between methylmercury and increasing heart rate92, whereas two studies among Inuit in Greenland showed no associations between blood pressure and persistent organic

Conclusion

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pollutants93 and methylmercury94.

Most evidence supports a similar incidence of coronary heart disease and a higher incidence of cerebrovascular disease among Arctic Inuit compared to western populations. While it is indisputable that the social transition in circumpolar Inuit populations affects most risk factors for

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CVD, the association is obviously complex with an increase in some risk factors and a decrease in other risk factors over time. Factors that may increase CVD risk include ageing of the populations,

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genetic susceptibility, a rapid increase in obesity, diabetes and hypertension parallel with a decrease in physical activity and deterioration of the lipid profile. In contrast, and of great importance, there has been a marked decrease in smoking and alcohol intake, at least documented in Greenland, and contaminant levels are declining. Although there have been marked socio-economic and dietary changes, it remains unsolved and to some extent controversial how this may have influenced cardiovascular risk among Inuit.

The increase in life expectancy in combination with improved prognosis for patients with manifest CVD will inevitably lead to a large increase in the absolute number of people affected by CVD in

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ACCEPTED MANUSCRIPT Arctic Inuit populations. Additionally, time trends in most CVD risk factors point towards a contribution to a rise in CVD burden. For preventive purposes and for health care planning it is crucial in the future to carefully monitor disease incidence and risk factor trends in this vulnerable

Funding Sources

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No external funding was received for the present study

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Arctic population.

Disclosures

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The authors have no conflicts of interest

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ACCEPTED MANUSCRIPT Table 1. Prevalence of smoking in Inuit populations

15-17

1993-2012 1992, 2011

65-84% 70%, 92%

1997, 2003-2013 1997

39%-50%, 32%-88% 39%- 44%

2003-2007

67% - 79%

18, 19

20, 21-22 20

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ACCEPTED MANUSCRIPT Table 2. Prevalence of diabetes from clinical population surveys Year

50

1962 1983 52 1992 53 1994 55 1999 54 1994-2010* 12 2004 56 2005-10 *result from 4 combined cohort studies

Prevalence

Greenland Siberia Alaska Alaska Greenland Alaska Canada, Nunavik Greenland

0.06% 4.9% 4.7% 6.6% 9.7% 3.0% 9.1% 9.0%

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ACCEPTED MANUSCRIPT Figure legend

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Figure 1. Map of circumpolar peoples. From CIRCUMPOLAR HEALTH ATLAS University of Toronto Press, Scholarly Publishing Division © 2012. Reproduced with permission from W. Dallmann, Norwegian Polar Institute.

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