By Mercy Kagoda, MD, MPH

Preventive Medicine Physician, Lotus Integrative Medicine, Santa Monica, CA

Dr. Kagoda reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • An 80-year-old Tsimané has the vascular age of an American in his mid-50s.
  • Compared to an unselected U.S. population, the coronary atherosclerosis findings translate to a 28-year lag for Tsimané before reaching a coronary artery calcium score of 100.

SYNOPSIS: Tsimané, a population living in the Bolivian Amazon, have the lowest prevalence of coronary artery disease among any population studied; individuals 40 years of age have mean low-density lipoprotein and high-density lipoprotein of 91 mg/dL and 39.5 mg/dL, respectively, despite a high inflammatory burden from parasites and pathogens.

SOURCE: Kaplan H, et al. Coronary atherosclerosis in indigenous South American Tsimané: A cross-sectional cohort study. Lancet 2017;389:1730-1739.

Cardiovascular disease (CVD) is the leading cause of death globally and in the United States, with nearly one in every three deaths attributable to CVD.1 In 2013, of 54 million global deaths, 17.3 million were from CVD.2 Total costs of CVD were approximately $320 billion in 2011.3 Coronary atherosclerosis is a disease with fixed risk factors, such as genetics/family history, and modifiable risk factors, including hypertension, lipid/cholesterol profile, cigarette smoking, abdominal obesity, hypertension, alcohol intake, diabetes, and physical inactivity.2 Almost 50% of the coronary artery disease risk is reduced after adopting a heart-healthy lifestyle, even in the face of high genetic susceptibility to heart disease.4

Industrialization has been associated positively with an increase in the prevalence of coronary artery disease. However, research on mummies observed that populations that lived prior to industrialization demonstrated peripheral atherosclerosis, confirmed by calcium deposits in arteries. In these populations, the hypothesis is that high levels of inflammation from infection and an abundance of risk factors led to the development of atherosclerosis.

Kaplan et al measured the CVD risk factors, inflammatory burden, and coronary artery calcium (CAC) scores in a contemporary pre-industrial population to determine the prevalence of atherosclerosis in the setting of a high infectious inflammatory burden. The study was carried out between July 2014 and September 2015 on Tsimané, a population from Bolivia living along a tributary of the Amazon river. Tsimané live a forager-horticultural village lifestyle in thatched roof huts in communities of 60 to 200 people. Tsimané diet consists of 72% unprocessed, complex carbohydrates and wild fruits, 14% fat and 14% protein from nuts and seeds, and wild game caught from hunting with bows and arrows or fishing with arrows, lines, or nets. The complex carbohydrates are from slash-and-burn horticulture growing corn, plantains, manioc/cassava, and rice. Hunting sessions last more than an eight-hour workday and cover more than 11.18 miles (23,600 steps). Tsimané spend an average of four to seven hours per day in physical activity, with < 10% of their waking time spent sedentary. In contrast, more than 50% of Western waking time is sedentary.

The Tsimané Health and Life History Project team and the HORUS study team joined together to analyze data of 705 Tsimané individuals out of a population of 16,000 from 85 villages. Prior census results identified 1,214 individuals to be approximately older than 40 years of age. A random number generator was used to select the studied communities. Community rather than individual random selection was used, because it was more culturally appropriate and individuals wouldn’t feel singled out.

In this study, 416 of the 1,214 individuals were not in the randomly selected sample communities, and 67 people were not available for scanning for various reasons. The researchers scanned 731 individuals, and data were missing for 26 individuals. Complete data were available for 705 individuals, 72 of whom showed incidental TB findings and were referred to appropriate specialists.

The researchers obtained fasting morning blood draws, including lipids, apolipoprotein A and B, oxidized low-density lipoprotein (LDL), high-sensitivity C-reactive protein (hs-CRP), nine cytokines, erythrocyte sedimentation rate, white blood cell differential, and glucose. Framingham risk scores also were calculated to estimate the 10-year cardiovascular risk of each individual. A 16 detector row scanner and a licensed radiological technician obtained single ECG gated scan under supervision of a cardiologist team.

CAC scores are a measure of the calcified plaque in the coronary arteries, providing proof of coronary artery disease. The CAC score measures approximately one-fifth of the total atherosclerosis burden, as the non-calcified plaque is not measured.5 Non-calcified plaques currently are not measured in clinical practice, as the software is still under research investigation. In current clinical practice, obtaining CAC scores in low-risk individuals is not recommended.

Tsimané CAC scores (in broad age categories) representing a contemporary pre-industrial population were compared with contemporary industrial population-based studies in the United States (Multi Ethnic Study of Atherosclerosis, MESA). Tsimané CAC scores also were compared with populations from Germany (Heinz-Nixdorf Recall) and Japan. CAC scores are stratified as: 0, almost no risk; 1-99, low risk; 100-399, moderate risk; and > 400, high risk.

Multivariate, zero-inflated, negative binomial regression was used to assess the association between Tsimané CAC scores and coronary artery disease risk factors (while controlling for age and sex), and logistic regression was used to test for factors that inflate CAC absence.

Akaike’s information criteria were used to assess the fit of the model used to approximate this unknown reality. Incident rate ratio was used to indicate the proportional change in risk for each of the dependent variables. A ratio < 1 indicated decreased risk while a ratio > 1 indicated increased risk.

Baseline participant characteristics showed an average age of 58.7 years. The participants were approximately half female and half male, with an average body mass index of 24.1 kg/m2 and an average body fat of 22.1%. Average systolic blood pressure was 116/73.4 mmHg, with a mean resting heart rate of 65.9 beats per minute. Older people had slightly higher systolic blood pressures and resting heart rates. Total mean cholesterol was 150.81 mg/dL, high-density lipoprotein (HDL) was 38.67 mg/dL, LDL was 92.81 mg/dL, and triglycerides were 106.28 mg/dL. The average hs-CRP was 3.7 mg/L and erythrocyte sedimentation rate was 22 mm/h. The prevalence of coronary artery disease risk factors (hypertension, high cholesterol, elevated blood sugars, obesity, and smoking) was very low across all age groups.

There was a very low baseline of coronary atherosclerosis as measured by CAC scoring. Of the 705 individuals with complete data, 596 had CAC scores of zero, 89 had CAC scores of < 100, 20 had scores of 100, and only one individual had a score > 400.

After 75 years of age, 65% (38 of 48) of Tsimané individuals did not have CAC and only 8% had moderately increased calcium scores. Although Tsimané men had slightly higher CAC scores than Tsimané women, Tsimané men still had lower CAC scores than Japanese women who, until now, had the lowest reported CAC scores. In stark contrast, only 14% of the U.S. MESA population did not have any coronary artery calcium, and more than 50% had CAC scores of at least 100 Agatston units.

Not surprisingly, in this study, younger age, female gender, and lower triglycerides were associated with lower CAC. Body fat and hs-CRP were associated with higher CAC scores, but higher monocyte counts were associated with lower CAC scores.

COMMENTARY

In the United States, the American Heart Association, the National Cholesterol Education Program, and the American College of Cardiology recommend obtaining a CAC score for people in the intermediate risk category of the Framingham CVD risk prediction algorithm.6 Obtaining a CAC score is considered to be most beneficial for patients in the intermediate risk category with undiagnosed chest symptoms and or equivocal results from other noninvasive testing and is not recommended for asymptomatic low-risk individuals.6 The CAC score can be transformed into arterial age at which the individual’s CVD risk is equal to that of the observed CAC score.7 It is alarming that an 80-year-old Tsimané is the vascular equivalent of a 50-year-old American.

National Lipid Association guidelines and National Cholesterol Education Program guidelines are similar for cholesterol in low-risk individuals, where LDL-c of < 100 mg/dL is considered desirable.8,9 The average LDL-c in Tsimané would meet both these recommendations. However, perhaps the recommendation for a total cholesterol of < 200 mg/dL in low-risk individuals should be lowered further to < 160 mg/dL to achieve an even lower prevalence of coronary artery disease as seen in Tsimané.

In other cross-sectional studies of contemporary pre-industrial societies, such as Kalahari bushmen, Tarahumara, rural Chinese, and Okinawans who consume a primarily plant-based diet, very low rates of CVD were noted.10 Cholesterol levels are also lower. For example, in the Tarahumara, average total cholesterol is 136 mg/dL, and in populations from rural China, average total cholesterol is 127 mg/dL.10,11 Dietary approximations of 13% protein, 75% carbohydrates, and 12% fats in the Tarahumara11 are similar to the percentages of Tsimané.

Interestingly, the same risk factors, such as younger age, female sex, lower triglycerides, and body fat, affect both Tsimané and the U.S. population. However, the degree to which the CAC worsened with age was moderated in Tsimané because of the lower incidence of risk factors. However, because of the low prevalence of CVD in Tsimané, the zero-inflated, negative, binomial model explained 19% of the outcome: CAC score. This model included age, sex, body fat, and hs-CRP and did not include diet and physical activity. Perhaps if it had included diet or physical activity, the percentage explaining the outcome could have been much higher. It would be interesting to analyze the MESA data similarly to compare the model predictions of CAC scores in a different society.

Despite the high inflammatory burden from pathogens and parasites, Tsimané still were protected against coronary artery disease. Interestingly, helminth infections were associated with lower CAC scores even though more than 90% of adults at cross-sectional sampling suffered from helminth infections. The most common helminth infections in Tsimané include hookworm, Ascaris lumbricoides, and Giardia lamblia. Earlier studies have suggested that helminths may protect against heart disease and type 2 diabetes because they decrease total cholesterol by using the host’s cholesterol for their own use, lower blood glucose by consuming the hosts glucose, and shift the inflammatory response toward a type 2 helper (TH2) cell response.12 A TH2 response is characterized by high IL-10 (which is anti-inflammatory), IL-5 levels, and other interleukins. The data from Tsimané offer further evidence to suggest that the type of immune response activated by infection or autoimmune disease is key.

The authors acknowledged the key limitations of the study, such as using CAC without contrast as a direct measure of coronary atherosclerosis, which would preclude assessment of non-calcified plaque reconstruction. They also acknowledged the possibility of ecologic fallacy in which aggregate risk factors may not translate into individual risk factors. Further genetic analysis is still underway (M Gurven, PhD, personal communication, July 7, 2017). However, epidemiological data suggest that Tsimané may not have a genetic protective effect. This is reflected by slight increases, over the past 10 years, in biomarkers (increasing blood sugars, cholesterol, weight, and body fat) in relation to changes in the environment of increased sugar consumption and decreased physical activity. If Tsimané did have genetic protective effects such as those seen in people with PCSK9 mutations, their cholesterol levels would be more consistent despite the changing environment.

Not surprisingly, the individual with a CAC score > 400 had blood pressure 140/88 mmHg, CRP 4.11 mg/dL, body fat 36.6%, weight 65 kg, height 145 cm, LDL 183, HDL 30, and was a 69-year-old female from a more acculturated village (M Gurven, PhD, personal communication, July 7, 2017).

Overall, this was a very interesting cross-sectional study with a high percentage of community involvement — more than 50% of the community was sampled. The findings agreed with prior studies of populations having very low CVD prevalence, eating mostly plant-based diet, having low cholesterol, obtaining plenty of physical activity, abstaining from smoking, and having normal BMI, low blood pressure, and low blood glucose.

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