Elsevier

Thrombosis Research

Volume 187, March 2020, Pages 159-165
Thrombosis Research

Full Length Article
High-intensity interval training recuperates capacity of endogenous thrombin generation in heart failure patients with reduced ejection fraction

https://doi.org/10.1016/j.thromres.2020.01.013Get rights and content

Highlights

  • HFrEF reduces capacity of TG by diminishing blood cell-derived MP counts.

  • HFrEF increases vascular endothelial shedding and circulatory oxidative stress.

  • HIIT alleviates HFrEF-related TG reduction and vascular endothelial damage.

  • HIIT depresses HFrEF-induced oxidative stress/pro-inflammatory status.

Abstract

Objective

Consumptive coagulopathy is associated with increased mortality in patients with heart failure (HF). Physical activity influences the risk of major vascular thrombotic events. This study investigates how high-intensity interval training (HIIT) affects the capacity of endogenous thrombin generation (TG) by modulating circulatory procoagulant microparticles (MPs) in HF patients.

Methods

Thirty-eight HF patients with reduced ejection fraction (HFrEF) and 38 age- and gender-matched normal counterparts (NC) were recruited into this study. The HFrEF group performed HIIT (3-min intervals at 40% and 80%VO2peak) on a bicycle ergometer for 30 min/day, 3 days/week for 12 weeks, whereas the NC group did not receive any form of intervention. Plasma TG kinetics, procoagulant MPs, coagulation-related factors, and oxidative stress/proinflammatory status were analyzed.

Results

The HFrEF group exhibited (i) less endogenous thrombin potential (ETP) and TG rate, (ii) lower concentration/activity of tissue factor (TF) and counts of TF-rich MPs derived from blood cells, and (iii) higher vascular endothelial shedding and plasma myeloperoxidase and interleukin-6 concentrations, compared to the NC group did. However, HIIT elevated TG rate and TF concentration/activity in plasma, as well as, TF-rich MP counts derived from blood cells in patients with HFrEF. Moreover, the exercise regimen also decreased vascular endothelial shedding and plasma myeloperoxidase and interleukin-6 concentrations in HFrEF patients.

Conclusion

HFrEF reduces the capacity of endogenous TG in plasma, which is associated with decreased (or consumed) circulatory procoagulant MP levels. However, HIIT alleviates HFrEF-declined endogenous TG capacity and vascular endothelial damage through recuperating TF-related coagulation activity and suppressing oxidative stress/proinflammatory status.

Introduction

Ischemic etiology of the cardiomyopathy and lower ejection fraction (EF) were found to be independent predictors of systemic embolization [1]. A clinical investigation has reported that heart failure patients with reduced ejection fraction (HFrEF) have higher crude rates of thrombo-embolism, compared with those of HF patients with preserved ejection fraction (HFpEF) [2]. Moreover, HFrEF patients with an embolic event suffered a significantly higher mortality (38.9%) during the follow-up period when compared to those without an embolic event (10.3%) [3]. Advanced HF predisposes to the development of consumptive coagulopathy [[4], [5], [6]], whereas low plasma concentrations of coagulant factors are associated with increased risk of mortality in patients with HF [7]. Thrombin activity is critical to determining the severity of hemostatic reactions [8]. The procoagulant microparticles (MPs) derived from blood cells can effectively trigger thrombin generation (TG) [9]. Our recent investigation showed that elevated oxidative stress and further consequence of vascular endothelial damage leaded to the development of consumptive coagulopathy, which contributed to attenuated capacity of endogenous TG in patients with HF [10]. Accordingly, regional tissue ischemia, stagnant blood flow, elevated oxidative stress, and/or imbalanced neurohormonal factors may confer to the development of consumptive coagulopathy in patients with HF [[4], [5], [6]].

Regular exercise improves cardiopulmonary fitness and reduces the risk of major vascular thrombotic events [11,12]. However, physical activity imposes, paradoxically, both enhancing and suppressing effects on thrombogenesis, depending on the type and intensity of exercise [11]. An early study demonstrated that warm­up exercise (40%VO2max) reduce high-intensity exercise (80%VO2max)-induced risks of inflammatory thrombosis associated with leukocytes and platelets, which is a form of preconditioning [13]. Recently, our investigation further revealed that high-intensity interval exercise training (HIIT) that consists of alternating mild-(40%VO2max) and high-(80%VO2max) intensity exercise significantly suppressed hypoxia-induced inflammatory thrombosis in healthy sedentary men [14]. However, no clear and comprehensive pictures of HIIT effects on endogenous TG capacity and blood coagulation in HFrEF patients have become available.

To answer the above questions, this investigation evaluated the effects of HIIT on (i) the concentrations or activities of coagulation-related factors in plasma, (ii) the levels of vascular endothelial shedding and circulatory procoagulant MPs, (iii) the kinetic properties of endogenous TG in plasma, and (iv) the levels of plasma peroxide and proinflammatory cytokine in HFrEF patients. The aim of the present study is to establish an effective exercise strategy for improving aerobic capacity and simultaneously retarding the development of consumptive coagulopathy in patients with HFrEF.

Section snippets

Subjects

This study enrolled 38 patients diagnosed with HFrEF from August 2015 to July 2017 in the Heart Failure Center, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan. HFrEF was diagnosed if the patients had a left ventricular ejection fraction (LVEF) <40%. All HFrEF patients were New York Heart Association (NYHA) functional class II or III and had received optimal treatment for at least 12 months according to American Heart Association/American College of Cardiology

Cardiopulmonary fitness and hematologic parameters

All NC and HF subjects have no occurred thrombotic events, rehospitalization, and death throughout experimental periods (Table 1). Regarding myocardial contractility, the HIIT regimen resulted in significantly elevated left-ventricular ejection fraction (LVEF) from 35% to 42% (Table 1, P < 0.05) in patients with HF. However, hematological parameters (i.e., erythrocyte, hemoglobin, hematocrit, leukocyte, and platelet) did not change significantly after 12-week HIIT in the HFrEF group (Table 1).

Discussion

This investigation clearly demonstrates that HFrEF reduces the amount and rate of TG in plasma by diminishing the levels of blood cell-derived procoagulant MPs and coagulation-related factors. However, HIIT for 12 weeks alleviates HFrEF-induced endogenous TG reduction and vascular endothelial damage through recuperating blood coagulation activity and suppressing oxidative stress/proinflammatory status.

Previous studies have demonstrated that circulating MPs released from blood cells act as

Study limitations

Major limitations of this study are the lacks of D-dimer measurement that directly reflects the phenomenon of consumptive coagulopathy and the design of control HFrEF group that these patients only receive general healthcare without exercise training. However, a previous study indicated that the analysis of endogenous TG kinetics is superior to traditional D-dimer measurement [32]. Despite the lack of control HFrEF design, this study compared the differences in blood coagulation between HFrEF

Conclusions

The progression of HFrEF may impair the kinetic properties of endogenous TG, which is associated with decreased levels of blood cell-derived procoagulant MPs and depressed activation of coagulation pathway. However, HIIT for 12 weeks alleviates HFrEF-induced endogenous TG reduction and vascular endothelial damage through recuperating blood coagulation activity and suppressing oxidative stress/proinflammatory status. These findings provide a new insight into how HIIT alleviates dysfunction of

Author contribution

Jong-Shyan Wang was involved in conception and design of research; Chih-Chin Hsu, Tieh-Cheng Fu, and Shu-Chun Huang performed experiments; Jong-Shyan Wang and Chih-Chin Hsu analyzed data, interpreted results of experiments, prepared the figures and drafted the paper; Jong-Shyan Wang and Chih-Chin Hsu edited and revised the paper; Jong-Shyan Wang, Chih-Chin Hsu, Tieh-Cheng Fu, and Shu-Chun Huang approved the final version of paper.

Funding sources

This work was supported by the National Science Council of Taiwan (grant number NSC 106-2314-B-182-048-MY3), Chang Gung Medical Research Program (grant number CMRPD3I0021), and Healthy Aging Research Center, Chang Gung University (grant number EMRPD1A0841).

Acknowledgments

The authors would like to thank the volunteers for their enthusiastic participation.

Declaration of competing interest

No conflicts of interest, financial or otherwise, are declared by the authors.

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  • Financial support: This study was supported by grants NSC106-2314-B-182-048-MY3, CMRPD3I0021 and EMRPD1A0841.

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