Brown Bears (Ursus arctos) Seem Resistant to Atherosclerosis ­Despite Highly Elevated Plasma Lipids during Hibernation and Active State

Introduction

Hibernation is an extreme physiological challenge for the brown bear. For 5–7 months of the year metabolism is based mainly on lipids from stored fat while protein synthesis is reduced. The dependency on lipid metabolism during hibernation increases plasma lipids as documented in two American black bears (Ursus americanus) and one Asiatic black bear (Ursus thibetanus), ¹ four American black bears ² and two brown bears ³ —all kept in captivity. A recent study compared plasma lipids in seven captive and nine free‐ranging adult American black bears and although no sampling was done during hibernation, lipid concentrations were found to vary significantly among populations of black bears. ⁴ Despite the lack of information from free‐ranging bears, the overall conclusions from these previous studies are that not only are plasma lipid levels raised during hibernation, lipids are also generally elevated compared to human values.

In humans, plasma lipid concentrations and atherosclerosis are associated, as is also the case for various mammal models of atherosclerosis. ⁵ , ⁶ , ⁷ , ⁸ We have only been able to find one published account on atherosclerosis in bears, a case report of cerebrovascular atherosclerosis in an aged grizzly bear (Ursus arctos horribilis). ⁹

The objective of this study was to ascertain plasma concentrations of lipids in free‐ranging brown bears during hibernation and in the same bears while active. To establish whether the presumably high plasma concentrations of lipids cause atherosclerotic fatty streaks and plaque building we related the biochemical findings to coronary and aortic histopathology from bears shot in Sweden during the legal hunting season.

Methods

Results

Blood samples were collected from seven free‐ranging brown bears, (three females and four males, 2–3 years old). Material for histological investigation was obtained from 12 brown bears (six females, six males), between 1.5 and 12 years old (mean 4.6 ± 0.7 years), weighing 101.6 ± 14.5 kg. Samples from these bears shot during hunting were collected between 1.5 and 7 hours post mortem (mean 3.0 ± 0.4 hours).

Total plasma cholesterol decreased in all bears from hibernation to the active summer period (11.08 ± 1.04 mmol/L vs. 7.89 ± 1.96 mmol/L, P= 0.0028, Figure 1A ) as did triglyceride (3.16 ± 0.62 mmol/L vs. 1.44 ± 0.27 mmol/L, P= 0.00012, Figure 1D ) and LDL cholesterol (4.30 ± 0.71 mmol/L vs. 2.02 ± 1.03 mmol/L, P= 0.0075, Figure 1B ). There was no statistically significant difference between the two conditions regarding HDL cholesterol (4.78 ± 0.59 mmol/L vs. 4.95 ± 0.51 mmol/L, P= 0.18, Figure 1C ). Blood hematocrit was higher during hibernation (56.8% vs. 45.0%, P= 0.00013).

Aortas were examined from 11 animals. The average wall thickness was around 5 mm with slight tapering toward the aortic arch; there was a definite thinning when reaching neck arteries, the thickness of those were 2–3 mm. Left anterior descending coronary artery sections were obtained from all 12 bears. The wall thickness was about 1–1.5 mm.

Discussion

This study represents the first systematic comparison of plasma lipids in hibernating and active free‐ranging brown bears and the first description of aorta and coronary artery histopathology in this species. Our main findings were that brown bear plasma lipids are elevated during hibernation compared with active state and that cholesterol levels generally are much higher than normal human values. Furthermore, bears up to 12 years old show no signs of atherosclerosis—not even fatty streaks.

The most probable source of increased plasma lipids is from stored triglycerides deposited in adipose tissue. Lipid oxidation of this fat is the primary fuel in bears during hibernation and the increase in cholesterol and triglycerides may be viewed as an alteration in the metabolism of lipoproteins responsible for clearance of these lipids. ² Hematocrits were higher during hibernation and hemoconcentration likely contributed to the increase in cholesterol but can only explain part of the rise in this parameter.

Previous studies have documented increasing cholesterol levels in captive American black bears during hibernation. ¹ , ² Nelson et al. measured cholesterol in plasma and found levels in the same range as we (total cholesterol of 13.4 mmol/L in winter and 9.6 mmol/L in summer) (1). In contrast, Hissa et al. reported higher cholesterol values during summer than winter in two captive brown bears. ³ Although Frank et al. measured cholesterol in wild American black bears they did not include hibernation sampling. ⁴ Chauhan et al. ² analyzed serum and not plasma and used a different analysis technology (thin layer chromatography) thus hindering direct comparisons with our findings. Despite considerable variation in food patterns and physical activity between free‐ranging and captive bears, the findings of the present study corroborate that brown bear plasma lipids are elevated during hibernation and that the levels generally are considerably higher than what is normally found in humans. The bears in this study had very high plasma concentrations of HDL cholesterol compared to humans. Although low HDL concentrations are associated with increased risk of cardiovascular disease in humans, recent findings question the protective role of high HDL levels. ¹⁵

Although seasonal variations and inactivity influence lipid levels, this is not confined to hibernators. In healthy humans total cholesterol peaks in December–January although the total seasonal variation is around 0.1 mmol/L only with changes in plasma volume accounting for much of the variation. ¹⁶ Two bed rest studies in humans, one lasting 35 days ¹⁷ and one lasting 20 days ¹⁸ both documented an HDL cholesterol decrease and a triglycerides increase in relation to bed rest. However, these changes are far from the drastic alterations in the same variables in brown bears. Although sedentary life style and high cholesterol levels are powerful risk factors for cardiovascular disease in humans, our histopathological findings indicate that brown bears are relatively resistant to atherosclerosis. This observation seems even more remarkable when considering that during hibernation heart rate, and thus blood flow, is reduced dramatically. In captive grizzly bears average resting heart rate is reduced from 84 to 17 beats per minute from active state to hibernation despite unchanged stroke volume. ¹⁹ When blood flow is reduced fluid shear stress is also typically reduced, and low shear stress in blood vessels is related to the forming of atherosclerotic plaques. ²⁰ But another risk factor in the atherosclerotic process—oxidative stress—is increased in hibernating American black bears ²¹ and adds to the picture of bears as unique biological models.

The instrument and methods used in this study are routinely used for measuring blood levels of total cholesterol, LDL, HDL, and triglycerides in human samples. To the best of our knowledge, the methods have not yet been validated for use in bears. However, in veterinary clinics identical analyses, using the same instruments and reagents, are routinely performed in a wide variety of animal species (e.g., horse, monkey, and lizard). Our methodology for measuring LDL cholesterol is not a routine veterinary technique, but is also an enzymatic colormetric method, which must be considered reliable irrespective of species. It is a limitation to our study that plasma lipid measurements were done in one group of bears whereas histopathology was investigated in another group. However, the last group was older, thus increasing the chance of detecting atherosclerotic changes. As cholesterol levels rise with age in humans ²² we have no reason to believe that cholesterol levels were lower in the bears shot during hunting. One could argue that the histopathological examinations were done in bears too young to develop atherosclerosis. However, brown bears typically reach reproductive maturity before the age of 5 years and rarely live to after the age of 25. ²³ Human data supports that early findings of atherosclerosis can be present at a very young age. ²⁴ Had we also measured additional fatty acids and lipoprotein lipase (lipogenic) or hormone‐sensitive lipase (lipolytic) we could have speculated in the causes of raised cholesterol in bears, but this was outside our scope.

Conclusion

We conclude that brown bear total cholesterol and triglyceride levels peak during hibernation and are considerably higher than human levels. Despite this and regardless of exposure to other factors constituting risks for development of cardiovascular disease in humans (obesity, physical inactivity, and circulatory slow flow during hibernation) we found no signs of atherosclerosis in brown bears. We hypothesize that brown bear resistance to atherosclerosis may serve as a biological model for prevention of cardiovascular disease in humans. Future studies must determine the biological mechanisms behind this resistance and whether for example the inflammatory or antioxidant defense systems, cholesterol recycling, endocrinological changes, or perhaps even how bears handle mental stress could improve our understanding.

Conflict of Interests

The authors declare that they have no financial, personal, or professional associations that could be perceived as interfering with the objectivity of the study.