Cardiovascular resistance to thrombosis in 13-lined ground squirrels

Abstract

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) enter hibernation as a survival strategy during extreme environmental conditions. Typical ground squirrel hibernation is characterized by prolonged periods of torpor with significantly reduced heart rate, blood pressure, and blood flow, interrupted every few weeks by brief interbout arousals (IBA) during which blood flow fluctuates dramatically. These physiological conditions should increase the risk of stasisinduced blood clots and myocardial ischemia. However, ground squirrels have adapted to survive repeated bouts of torpor and IBA without forming lethal blood clots or sustaining lethal ischemic myocardial damage. The purpose of this study was to determine if ground squirrels are resistant to thrombosis and myocardial ischemia during hibernation. Blood markers of coagulation, fibrinolysis, thrombosis, and ischemia, as well as histological markers of myocardial ischemia were measured throughout the annual hibernation cycle. Hibernating ground squirrels were also treated with isoprenaline to induce myocardial ischemia. Thrombin-antithrombin complex levels were significantly reduced (p < 0.05) during hibernation, while D-dimer level remained unchanged throughout the annual cycle both consistent with an antithrombotic state. During torpor the ground squirrels were in a hyperfibrinolytic state with an elevated ratio of tissue plasminogen activator complexed with plasminogen activator inhibitor to total plasminogen activator inhibitor (p < 0.05). Histological markers of myocardial ischemia were reversibly elevated during hibernation with no increase in markers of myocardial cell death in the blood. These data suggest that ground squirrels do not form major blood clots during hibernation through suppression of coagulation and a hyperfibrinolytic state. These animals also demonstrate myocardial resistance to ischemia.

Integrated transcriptomics and metabolomics reveal protective effects on heart of hibernating Daurian ground squirrels

“…CK‐MB plays an important role in cellular energy metabolism, and therefore a decrease in CK‐MB was consistent with reduced energy requirements of the heart and muscle during hibernation (Abnous & Storey, 2007; Barrows et al, 2011). The finding that cTnI was significantly higher in 13‐lined ground squirrel plasma in the IBA group as compared with the LT group supported our findings (Bonis et al, 2019). Therefore, we assumed that the dynamic changes in cTnI seen over torpor‐arousal cycles indicated the adaptive response of the myocardium, in which the myocardial cells were able to repair themselves and gradually restore their normal function after repeated I/R injury.…”

Hibernation and hemostasis

“…Upon fibrinolysis, fibrin in a clot is cleaved into fibrin degradation products, of which D-dimers can be detected in plasma and is commonly used in the diagnosis of venous or arterial thrombosis. In bears, hamsters, and ground squirrels no increases in D-dimers are seen during hibernation, consistent with low levels of clot formation and fibrinolysis (Iles et al, 2017;Bonis et al, 2019). The lack of D-dimers is consistent with suppression of secondary hemostasis and absence of actual clot fibrinolysis during torpor, while the hyperfibrinolytic state reflected by increased tPA and PAI-1 may be an added layer of protection in the event that a clot does form (Figure 7).…”

“…An alternative to reducing clotting Frontiers in Physiology frontiersin.org factors would be to increase anticoagulants. Yet, the anticoagulant proteins antithrombin and protein C are not reduced in torpid hamsters and ground squirrels (Bonis et al, 2019). However, in hibernating bears antithrombin levels are reduced, but it is not known if this is due to decreased production of antithrombin or increased consumption (Welinder et al, 2016).…”

Hepatic lipid droplet breakdown through lipolysis during hibernation in Chinese Soft-Shelled Turtle (Pelodiscus sinensis)

“…Using brown bears ( Ursus arctos ), the researchers found that winter bear serum could reduce the protein turnover of myotubes, thereby maintain muscle mass and strength during hibernation, and it might be useful for developing new tools to fighting human muscle atrophy [30]. In 13-lined ground squirrels ( Ictidomys tridecemlineatus ) [31], thrombosis and myocardial ischemia do not occur during hibernation (during which non-hibernating animals are more likely to get thrombosis and myocardial ischemia). This phenomenon indicates that hibernating mammalian animals are natural cardiovascular disease research models.…”